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Change Requests - eSubmission - Europa

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									EU Region Question & Answer and Electronic Submission Specifications & Guidances Change
                                  Request Document

                                                     Version 1.25.4

                                                         March 2011

                                Document Change History presented with most recent first
                  Version Number        Date                                          Description
               Version 1.25.4         11-Mar-11                     Updates from CCB mtg: Revisions incorporated
               Version 1.25.3         10-Mar-11                          Pre-CCB mtg: Revisions incorporated
               Version 1.25.2         9-Mar-11                         Pre-CCB mtg: New change requests added
               Version 1.25.1         7-Mar-11                  Pre-CCB mtg: New change requests added; dates added
               Version 1.25           3-Mar-11       Updates from TIGes mtg approval & post meeting Interlinking updates: CR's
                                                             'Rejected' and 'Completed' moved to respective spreadsheets
               Version 1.24.7         25-Feb-11               Post CCB mtg: updates received from Harmonisation Group
               Version 1.24.6         25-Feb-11                      Post CCB mtg: changes discussed at meeting
               Version 1.24.5         24-Feb-11                    CCB mtg pre TIGes: New change requests added
               Version 1.24.4         10-Feb-11   CCB mtg: Feedback from CCB members on CR-20110127-01 and EMA Business
                                                                                Group added.
               Version 1.24.3         3-Feb-11                     Pre-CCB mtg: New change requests added
               Version 1.24.2         12-Jan-11         CCB mtg: Updates to new and closed change requests; feedback from
                                                                            Harmonisation Group added
               Version 1.24.1         11-Jan-11   Pre-CCB mtg: New change requests added, Interlinking Dec mtg feedback added
                                                                             for 2 CRs, Q&A 23 added
               Version 1.24           10-Dec-10         Updates from TIGes mtg approval: CRs 'rejected' moved to respective
                                                    spreadsheets per TIGes Joint Meeting approval on 10-Dec-2010. Q&As 24-27
                                                                         approved & officially incorporated.
               Version 1.23.5         10-Nov-10    Pre-CCB mtg: New CR added, answers for Q&As formatted/inserted (25 & 26)

               Version 1.23.4         2-Nov-10        CCB mtg: Calendar of Meetings updated; New CRs added, updates from
                                                       Interlinking Group added in CR status and new Q&As added (28 & 29)
               Version 1.23.3         4-Oct-10    Pre-CCB mtg: New CR added, status updates from Harmonisation & Interlinking
                                                                    Groups added, Q&As from Interlinking added
               Version 1.23.2         3-Sep-10        Post-CCB mtg: new CRs disposition; revisions to Q&A and 'Deferred' tabs
                                                                                  proposed by CCB
               Version 1.23.1         3-Sep-10       Pre-CCB mtg: Additional CRs added, Q&A tab revised [Q&As addressed in
                                                  issued guidances moved to respective worksheets and removed from active Q&A
               Version 1.23           3-Sep-10                     TIGes mtg approval: move CRs noted as project
                                                     Updates from tab], updates to 'Deferred' CRs from eAF 'closed', 'duplicate' or
                                                   'rejected' to respective spreadsheets per TIGes Joint Meeting approval on 3-Sep-
                                                                                          2010.
               Version 1.22.2         1-Aug-10      Revised to add new change requests; will be discussed at next CCB meeting in
                                                                          September [post TIGes Joint meeting]
               Version 1.22.1          7-Jul-10   Revisions by CCB to follow-up on Open Change Requests; retired Q&A #10&12
                                                      [removed from table], changed order of sheet tabs, updated Introduction in
                                                          alignment with creation of CCB and added their Terms of Reference

               Version 1.22           4-Jun-10    Update following approval by TIGes 3 June 2010
               Version 1.21.2         10-May-10   Pre-assessment by trial CCB team
               Version 1.21.1         1-Jan-10    Inclusion of statement of clarification on EU M1 v1.4.1
               Version 1.21           1-Dec-09    Update following discussion of open CRs by TIGes subgroup, and general review
                                                  of status and presentation of all CRs. All closed/withdrawn/rejected/duplicated
                                                  CRs moved to new worksheets; all CRs implemented in EU M1 v1.4 moved to the
                                                  appropriate 'Implemented in EU M1 v1.4' worksheet. All CRs for a potential EU
                                                  M1 v1.4.1 (spec update only) identified and marked.

               Version 1.20           1-Nov-09    Update following discussion of some CRs at October Interlinking meeting.
                                                  Addition of new November CRs. Preparation for discussion November TIGes.
                                                  Preparation for sub-group review 10/12.
               Version 1.19           1-Sep-09    Inclusion of new CRs/QAs for consideration at September TIGes
               Version 1.18           1-Jun-09    Updated after TIGes of May 2009 to identify potential changes for EU M1 v1.4.
                                                  Version not published, but produced purely for distribution to TIGes and EU M1
                                                  drafting group to agree on scope.
               Version 1.17           1-May-09    Updated after Interlinking meeting of April 2009 and publication of updated
                                                  validation criteria May 2009, update of CP dossier requirements April 2009,
                                                  publication of Harmonisaed Guidance May 2009

               Version 1.16           1-Mar-09    Updated after Interlinking meeting review of all assigned CRs
               Version 1.15           1-Mar-09    CRs added for TIGes 35. Full review of outstanding change requests and
                                                  assignments. Introduction of colour coding for open/closed CRs
               Version 1.14           1-Dec-08    Comments from Interlinking Group on all CRs assigned to this group, and
                                                  comments from Dec. TIGes. Addition of CR-2008-12-10
               Version 1.13           1-Jun-08    CRs and QA 22 added for TIGes 33, general update after publication of EU M1
                                                  specification v1.3
               Version 1.12           1-Mar-08    Q&As 9, 12, 15-21 added confirmed after TIGes-J-32
               Version 1.11           1-Jan-08    More updates for publishing on EMEA e-subs website (whilst review of
                                                  CRs/Q&A is ongoing)
               Version 1.10           1-Jan-08    Further updates for publishing on EMEA e-subs website
               Version 1.9            1-Nov-07    Comprehensive addition of accrued change requests and review of summaries

               Version 1.8            1-Jun-06    Review of document carried out for TIGes
               Version 1.7            1-Mar-06    CRs 15-16-17-18 Added for TIGes-J-24
               Version 1.6            1-Dec-05    Updated after release of eCTD v1.1
               Version 1.5             Dec-05     Q&A 14 added
               Version 1.4            1-Nov-05    New Change Request 14 added
               Version 1.3            1-Sep-05    New Change Requests 09, 10, 11, 12, 13 added
               Version 1.2            1-Jun-05    New Change Requests and Q&A added, plus ICH Q&A referred for regional
                                                  advice
               Version 1.1            1-Sep-04    Change Request added (EFPIA)
               Version 1.0             1-Jul-04   Initial baseline after reviewing existing questions
                                                                                                    Introduction

This document is managed by the EMA eSubmission Change Control Board [CCB] which is authorized under the EMA mandate dated 20/06/2010, v 0.4. Current membership is listed below.

CCB Terms of Reference: The purpose of the eSubmission CCB is to accelerate decisions and resutls, improve the organisation and traceability of change requests, ensure follow-up of open items and improve
performance of change request at the Telematics Implementation Group electronic submissions [TIGes] meetings. The scope is all change requests for electronic submissions requirements and related guidances.


Purpose: This document is a summary of change requests which have been reviewed by the CCB on a monthly basis and by TIGes on a quarterly basis for the eCTD Specifications & guidances, PIM and electronic
Application Forms (eAF).

This document will be updated aafter the monthly CCB meetings and published after the TIGes quarterly meetings. Questions are listed with with an approved answer. Change control requests are listed with details
of the person, company or organisation who submitted the request, along with details of the actions taken and status of the request. Point people for the groups CRs are referred to are listed below.


Key to Change Requests Worksheet
Each change request or question received is numbered. A subset of the change request or question information is copied from the "European eCTD Standards Q&A and Change Request Form", including the name
and organisation of the person raising the request and the description of the change or the question in full. Any comments arising during the analysis of the issue by TIGes are recorded as well as the resulting Status
and Action(s).

Key to Q&A Worksheet
Each question is numbered. The question is written out in full and a reference to the change control procedure item that caused the question to be asked is listed. An official answer is given. The approval date for
the answer is listed.

CCB Membership
December 2010
Thomas Mauer, Programme Manager, EMA
TBD, RUP Manager, EMA
Pieter Vankeerberghan, Belgium
Klaus Menges, BfArm, Germany
Cynthia Piccirillo, EFPIA eCTD TG (Bristol-Myers Squibb)
Liesbeth Versteeg, EFPIA eCTD TG (Genzyme)
Katja Pecjak, EGA (Billev Pharma)

Interlinking Group
Miguel Bley, TIGes Chair

CMDH Harmonization Group
Karin Grondahl, Sweden

ICH M8 eCTD Implementation Working Group
TBD, EFPIA Topic Leader
TBD, EU Topic Leader
                                       Harmonisation
       CCB              Interlinking   Group         TIGes Joint
       Meetings         Meetings       Meetings      Meetings
2010   7-Jul            20-Jul
       2-Aug            17-Aug
       14-Sep           21-Sep         3-Sep         3-Sep
       14-Oct           19-Oct         8-Oct
       4-Nov            16-Nov         18-Nov
       2-Dec            14-Dec                       10-Dec
2011   12-Jan           18-Jan         12-Jan
       9-Feb & 23-Feb   15-Feb
       11-Mar           15-Mar         9-Mar         3-Mar
       14-Apr           12-Apr         6-Apr
       12-May           17-May         4-May
       1-Jun            21-Jun         1-Jun         8-Jun
       14-Jul           19-Jul
                        16-Aug
       1-Sep            20-Sep                       7-Sep
                        18-Oct
                        15-Nov
                        13-Dec                       2-Dec
                                                                                                                                                                                                                                                                                               EU eSub Change Requests

Pink = rejected;
Green = Completed;
Blue = New
         #                 Requestor                          Specification                                                                     Description                                                                                            Comments                                             Status                                      Due Date                Action                                              Group W here Action is   Implement in EU M1 Revision
                                                               Component                                                                                                                                                                                                                                                                                [where applicable]                                                          Sitting
  QA-20071022-01     Alastair Nixon GSK         Q&A variations document                        In the eCTD, how should an applicant handle multiple variations that occur in parallel and affect the same         Nov-07 Best Practice guide written for review and approval                                Accepted - refer to Interlinking Group                              Q&A document of variations to be updated.           Harmonisation Group      No
                                                                                               document?                                                                                                          March-09 : Subgroup to be established to address all issues of variation, in the          7/2010 - Follow-up with Interlinking                                Further discussion needed on who is
                                                                                                                                                                                                                  context of the new Variations Regulations. This CR will be addressed within this          Group                                                               responsible for Q&A document on variations
                                                                                                                                                                                                                  group.                                                                                    10/2010 - Interlinking Group - Proposal                             for eCTD. Proposal is to re-assign to the
                                                                                                                                                                                                                  7/2010 - EFPIA eCTD TG recommends to progress as a priority                               agreed. Q&A document of variations to                               Harmonisation Group
                                                                                                                                                                                                                  10/2010: Interlinking agreed on following :                                               be updated
                                                                                                                                                                                                                  CR is accepted. The Q&A document on eCTD Variations already refers to the issue
                                                                                                                                                                                                                  of submitting a consolidated sequence.
                                                                                                                                                                                                                  Additional clarification should be provided on the technical issues (i.e. use of
                                                                                                                                                                                                                  operation attributes).
                                                                                                                                                                                                                  The proposal of the Interlinking group is that the Q&A variation is updated to contain
                                                                                                                                                                                                                  information of parallel variations handling. Interlinking to refer CR back to CCB and
                                                                                                                                                                                                                  propose that responsibility is taken by Harmonisation sub-group.




  CR 20080909-01     Dietmar Boecker, Bayer     eCTD Guidance                                  Guidelines on the submission of the EU-RMP require a stand-alone format of the document including all                                                                                                        Accepted - refer to EMEA;                   Next major release      Refer to EMA eCTD Business Team for                 EMA                      No
                     Schering                                                                  annexes to be located in eCTD Module 1.8.2. This is in contradiction to the ICH eCTD requirements, that                                                                                                      7/2010 - Follow-up with EMA Business                                discussion and confirmation, and amend all
                                                                                               mandates a different location for most of the annexes.                                                                                                                                                       Group [G. Isakkson]                                                 guidance documents as appropriate.
                                                                                               In section 4.4 of the EU-RMP guideline EMEA/CHMP/96268/2005 it is outlined that the EU-RMP "should                                                                                                           10/2010 - transitioned to T. Mauer
                                                                                               be provided (...) in a stand-alone format allowing circulation to, and evaluation by pharmacovigilance and                                                                                                   2/2011 - on hold
                                                                                               risk management experts". The same requirement is defined by the Pre-Submission guide in response to
                                                                                               question 36. The template for the EU-RMP (EMEA/192632/2006) lists 8 Annexes, which should be
                                                                                               provided in eCTD Module 1.8.2 together with the main body of the RMP. However, some of the annexes like
                                                                                               the current SPC have already well defined locations in other Modules of the eCTD.
                                                                                               For the location of the EU-RMP annexes it is proposed to update the guidelines mentioned above, so that
                                                                                               applicants should cross refer from the EU-RMP to other locations of the eCTD where appropriate. With the
                                                                                               exception of the annex 1, all annexes would be affected:




    CR 20081008      Andrew Marr, GSK           eCTD Specification v 3.2                       The guidance just issued by QRD regarding production by the applicant of the PDF for final labeling is             Dec 08: EMEA meeting held to discuss issue - conclusion that requirements for             Accepted - refer to EMEA                    Next major release      Amend 'Questions and answers' relating to           EMA                      No
                     (EFPIA)                                                                   incompatible with the eCTD and will lead to duplication of effort.                                                 EMEA PDFs arise from the EMEA EPAR publication process, and eCTD                          7/2010 - Follow-up with EMA Business                                practical and technical aspects of the
                                                                                               In the longer term EMEA must align their requirements and if there is business logic for the filename as           filenaming requirements have a different purpose and support a different process          Group [G. Isakkson]                                                 implementation' to be updated
                                                                                               per the EPAR proposed name then an EU specification change may be justified with the inclusion an                  (review) and therefore requirements cannot be aligned until Q3 2009 when the              10/2010 - transitioned to T. Mauer
                                                                                               appropriate filename that meets ICH general filename requirements.                                                 EMEA publication process is re-designed. This conclusion was not readily                  2/2011 - on hold
                                                                                                                                                                                                                  accepted by industry - either alignment must be sought, or at least clear guidance
                                                                                               In the short-term there is an urgent need for clarification as to how an applicant can submit product              should be provided as to how to manage in the meantime, and a clear plan for
                                                                                               information inside and outside the eCTD, for all submission types without duplication of effort or risk of         resolution should be presented by EMEA
                                                                                               failure to validate or accept                                                                                      March 2009 : EMEA updated PDF naming convention within 'User guide on how to
                                                                                                                                                                                                                  generate PDF versions of Product Information' to be consistent with eCTD.
                                                                                                                                                                                                                  Practical Q&A needs to be updated to also reflect this change.
                                                                                                                                                                                                                  7/2010 - New version of naming guidance came out; practical Q&A also needed
                                                                                                                                                                                                                  updating to be aligned, belief that Claire Holmes had drafted




    CR 20090605      Alastair Nixon GSK         EMEA Post Approval Copy Requirements           The CP guidance was recently changed to ensure that CHMP members always get copies of all                          Text in parentheses in first line in table is changed to “(unless in eCTD format, then    Accepted - refer to EMEA;                   Next major release      Amend EMA post-submission guidance                  EMA                      No
                                                (EMEA/300339/2008)                             sequences so that they maintain a full lifecycle for the eCTD. However, the guidance says that the                 1 electronic copy via Eudralink (no CD/DVD required))”                                    7/2010 - Follow-up with EMA Business
                                                                                               electronic copy must be DVD or CD Rom (in the header of the table).                                                7/2010 - Completed in post-submission guidance, may need to update technical              Group [G. Isakkson]
                                                                                                                                                                                                                  guidance                                                                                  10/2010 - transitioned to T. Mauer
                                                                                               Eudralink can be used for communications less than 40MB, and although the general guidance for eCTD                10/2010 - Not accurate, needs to be revisited                                             2/2011 - on hold
                                                                                               states that Eudralink messages containing eCTD sequences should be followed up with a copy of the
                                                                                               submission on hard media (CD/DVD), an exception should be made for copies of sequences for Type 1A
                                                                                               and 1B variations to CHMP members. EFPIA members would all like to be able to use Eudralink only for
                                                                                               these submissions to CHMP members. Individual countries can then decide whether to process them into
                                                                                               an eCTD lifecycle locally, therefore keeping an up to date set of all sequences, or ignore them



   CR 20090605-II    Alastair Nixon GSK         EMEA Pre Submission Copy Requirements          Document has 2 missing footnotes, and requirements for individual modules for some countries which is              Footnotes should be added back if necessary and a comment “(full sequence if              Accepted - refer to EMEA                    Next major release      Amend EMA pre-submission guidance                   EMA                      No
                                                (http://www.emea.europa.eu/htms/human/pre      not possible when using eCTD                                                                                       eCTD)” is added to the entries identified.                                                7/2010 - Follow-up with EMA Business
                                                sub/dossierrequirements.pdf)                   The footnotes have gone (* in table header, ** for Czech Republic), and Austria, Bulgaria, Greece and                                                                                                        Group [G. Isakkson]
                                                                                               Slovakia need a CD Rom of just m1 and m2, which you would not and cannot do in eCTD format.                                                                                                                  10/2010 - transitioned to T. Mauer
                                                                                                                                                                                                                                                                                                            2/2011 - on hold
   CR 20090605-III   Alastair Nixon GSK         Distribution Requirements and Address          Statement requires PSUR in both MS Word and PDF. This is not common practice (EFPIA eCTD Topic                     Sentence should be removed.                                                               Accepted - refer to EMEA                    Next major release      Amend PSUR guidance                                 EMA                      No
                                                Lists for Periodic Safety Update Reports       Group surveyed May 2009), applicants tend to provide PDF only and have had no feedback from agencies to            7/2010 - In the absence of PV having access to the eCTD this needs to be                  7/2010 - Follow-up with EMA Business
                                                (PSURs)                                        the contrary.                                                                                                      addressed in business process                                                             Group [G. Isakkson]
                                                (Annex 6.2 of Volume 9A of the Rules                                                                                                                                                                                                                        10/2010 - transitioned to T. Mauer
                                                Governing Medicinal Products in the EU)        Statement at top of document: “CD-ROM means PDF + WORD format (i.e. two formats should be                                                                                                                    2/2011 - on hold
                                                EMEA/129976/2008                               submitted).” This is not common practice, nor should it be necessary as, with the right tools, it is possible
                                                                                               to cut and paste content from PDF documents.

    CR 20090512      Kevin Wing,                EMEA Implementation of electronic-only and     Change and clarification of when to use “To Be Advised” for the application number within an eCTD                  Discussed at TIGes, Sep-09.                                                               Accepted - refer to EMEA                    When M1 specification   Update EMA guidance and consider for eCTD           EMA/eCTD NMV/RPS         No
                     eCTDConsultancy            eCTD submissions: Q&As relating to             lifecycle                                                                                                          Referred to EMEA for initial guidance update (this is the document where this issue       7/2010 - With eCTD NMV group                is updated              NMV                                                 Subgroup
                                                practical and technical implementation July                                                                                                                       arose)                                                                                                                                                                                                            11/2010 - Requirements
                                                20th 2008                                      Recommended solution: place the following text on page 21 of the EMEA Implementation of electronic-only            Referred to eCTD NMV group for longer term solution.                                                                                                                                                              provided to ICH M8
                                                and eCTD EU M1 v1.3                            and eCTD submissions: Q&As relating to practical and technical implementation:

                                                                                               “Applicants should refrain from numbering initial variation application submissions, or any procedures for
                                                                                               which the exact application procedure number is not known. For variations, it is appropriate at least to
                                                                                               indicate the type of procedure, e.g. type IA, IB, II…but the procedure application number will only be given
                                                                                               upon receipt of a hard copy by the Agency and this number will be assigned to the eCTD submission as a
                                                                                               reference by EMEA, within the Agency‟s review system.”

                                                                                               With:

                                                                                               “For any submissions for which the full application procedure number is not known (e.g. initial submissions
                                                                                               of variations), applicants should populate the application procedure number with the core component of the
                                                                                               number i.e EMEA/H/C/XXX (which is consistent throughout the eCTD lifecycle)”

                                                                                               Part 2 (longer term)
                                                                                               When next updating the DTD of the EU M1 specification, implement a technical solution by creating 2
                                                                                               separate application number elements, one for the core component (e.g. EMEA/H/C/XXX or CC/H/XXX
                                                                                               etc) and one for the variable component. The variable component would only need to be included if known.

                                                                                               Note –refer to previous change requests CR-20080514, CR-20080514-01 and CR-20080514-05 for
                                                                                               outstanding issues around application number that are likely to impact implementation of this change.

  CR 20090512-01     Kevin Wing,                User guide on how to generate PDF              Question related to the filenaming of combined Product Information documents that are granulated per               Discussed at TIGes, Sep-09.                                                               Accepted - refer to EMEA                    Next major release      Agree on written solution                           EMA                      No
                     eCTDConsultancy            versions of the Product Information            strength/pharmaceutical form, following the recent update to the EMA‟s User guide on how to generate               Referred to EMA to answer as this is a specific issue for CP.                             7/2010 - Follow-up with EMA Business
                                                Guidance (with consideration of eCTD EU        PDF versions of the Product Information.                                                                                                                                                                     Group [G. Isakkson]
                                                M1)                                            The recently released version of the EMA‟s User guide on how to generate PDF versions of the Product                                                                                                         10/2010 - transitioned to T. Mauer
                                                                                               Information includes updates to bring the filenaming specification in line with the EU M1 eCTD guidance                                                                                                      2/2011 - on hold
                                                                                               (http://www.emea.europa.eu/htms/human/qrd/docs/52402007en.pdf).

                                                                                               An applicant may decide to granulate the combined Product Information per strength or per pharmaceutical
                                                                                               form and for the eCTD this will need to be reflected in the filename. Would the TIGes be able to provide
                                                                                               feedback on where the necessary text to provide this level of detail should be placed so that the filenames
                                                                                               are still inline with linguistic review requirements?



  CR 20090909-01     Hans van Bruggen,          EU M1 eCTD Specification v 1.4                 The EU m1 specification document uses the term “application” in ambivalent ways, namely to identify (1) a          Recommendation in CR form: The correct wording should be: “Files can be                   Accepted                                    When M1 specification   Include the Glossary from the EU harmonised         TIGes/EMA rapporteur     Yes
                     eCTDConsultancy B.V.                                                      full history of an eCTD, including all sequences pertaining the electronic common technical dossier and            referred to across modules (e.g. from Module 1 to Module 2) or across sequences           7/2010 - Follow-up with EMA Business        is updated              eCTD guidance, and include I the EU M1
                                                                                               (2) a single sequence/submission as part of an electronic common technical dossier. The specification              within the same eCTD; note however that it is not possible to refer to files in other     Group [G. Isakkson]                                                 specification. Review the use of all terms in EU
                                                                                               document should use unambiguous terms and use “application” consistently [Page 7 of the written                    eCTDs.”                                                                                   9/2010 - Owner of Module 1                                          M1 v1.4 according to this glossary, and update
                                                                                               specification]                                                                                                     It might be wise to add a glossary to the written specifications, the make the            specification is TIGes with EMA as                                  as necessary on next minor version.
                                                                                                                                                                                                                  difference between CTD/eCTD and submission/sequence. In addition the word                 rapporteur
                                                                                                                                                                                                                  application can be explained, being an act of applying for something. It is also          2/2011 - On hold per EMA
                                                                                                                                                                                                                  suggested to align with existing glossaries, such as the one for RPS.



  CR 20090909-02     Hans van Bruggen,          EU M1 eCTD Specification v 1.4                 The EU Module 1 specifications suggest that response documents are written per country in multi-country            Discussed by CR subgroup 20091210. Agree in principle with the proposal;                  Accepted - refer to Interlinking Group      When M1 specification   Update Module 1 specification                       TIGes/EMA rapporteur &   Yes
                     eCTDConsultancy B.V.                                                      submissions. This is incorrect.                                                                                    however this approach must be agreed by regulators. Decide whether responses              7/2010 - Follow-up with Interlinking        is updated              Q&A to be drafted.                                  Interlinking Group
                                                                                               1. For CPs, the country code is always “emea” and does therefore not bring any added value.                        are country-specific. There are places where emea' is synonymous with 'common'            Group                                       Q&A 10/19/2010
                                                                                               2. For bilateral phases during the MRPs and DCPs, the responses correspond to consolidated lists of                but these must be defined.                                                                9/2010 - Interlinking discussed;
                                                                                               questions and the country code is therefore always “common”.                                                       9/2010 - Agreed to keep DTD as is and amend the text in the M1 specification to           remains open until next edit. Owner of
                                                                                               3. For national phases following the MRP and DCP, the exchange of information on a faithful translation of         indicate that responses are 'common', not country specific.                               Module 1 specification is TIGes with
                                                                                               the common harmonised product information might be outside of the eCTD (i.e. eMail and telephone calls).           10/2010 - Interlinking agreed on following :                                              EMA as rapporteur
                                                                                               The eCTD will not be relevant at all.                                                                              CR is accepted.                                                                           10/2010 - Interlinking Group - Q&A to
                                                                                               4. For national procedures, the country code is not relevant at all.                                               Agreement is that responses are common documentation. However, the Interlinking           be drafted.
                                                                                               Hence, the country code should be removed from the written specifications as well as from the DTD.                 doesn't recommend an update of the specification to remove the variable components        12/2010 - Remco Munnik actioned to
                                                                                               [Page 33 and 34 of the written specification concerning Rows 67 and 68 of the Appendix 2                           in the response section.                                                                  draft
                                                                                               Page 43; eu-regional.DTD]                                                                                          Due to the fact that national translations can still be handled within the eCTD, the      2/2011 - M1 spec update on hold per
                                                                                                                                                                                                                  variable part will not be removed from the specification.                                 EMA

                                                                                                                                                                                                                  Remco Munnik will draft a Q&A document in which it is clarified that responses are
                                                                                                                                                                                                                  common documents and therefore common folder and variable part should be used.




  CR 20090909-03     Hans van Bruggen,          EU M1 eCTD Specification v 1.4                 As for the envelope of an eCTD for the CP, the EU M1 specifications do not allow to use “common” in the            Recommended: The correct wording should be: “For the Centralised Procedure, the           Accepted referred to EMA business           When M1 specification   Update Module 1 specification                       TIGes/EMA rapporteur     Yes
                     eCTDConsultancy B.V.                                                      ToC of an eCTD for the CP. However, this are two distinctly different topics. The omission of a common             country subdirectory is always named "emea" with or without “common” and……….”             team                                        is updated
                                                                                               envelope for attribute information is OK, whereas there are documents used in eCTDs which are                                                                                                                7/2010 - Follow-up with EMA business
                                                                                               considered common, irrespective of the procedure (CP, MRP/DCP or NP), such as many annexes to the                  Discussed by CR subgroup 20091210. it is believed that 'common' can be used for           group [G. Isakkson]
                                                                                               application form, such as:                                                                                         all parts of the dossier in CP, apart from in the envelope. Implement based on review     10/2010 - transitioned to T. Mauer
                                                                                               1. Certificate of Suitability on active substance                                                                  of change of EMEA to EMA (CR 20091203).                                                   2/2011 - On hold per EMA
                                                                                               2. Curriculum vitae of the qualified person for pharmacovigilance
                                                                                               3. Declaration from the qualified person
                                                                                               4. Manufacturing authorisation
                                                                                               5. Justification of multiple manufacturers for batch release
                                                                                               6. Flow-chart indicating all sites involved in the manufacturing process of the medicinal product or active
                                                                                               substance
                                                                                               7. GMP certificate
                                                                                               8. Ph. Eur Certificate of Suitability for TSE
                                                                                               9. Written consent on GMO release in the environment
                                                                                               10. Scientific advice given by -<agency name> <YYYYMMDD>
                                                                                               11. Copy of marketing authorizations
                                                                                               12. Correspondence on multiple applications
                                                                                               13. Orphan designation decision
                                                                                               14. List of product names and marketing authorization holders in CMSs
                                                                                               15. Conditions and documents to support the Type I variation
                                                                                               16. Supportive data package
                                                                                               17. Comparison document
                                                                                               This becomes particularly important to facilitate grouping of variations and work sharing across multiple
                                                                                               procedures without rework of the locations of these documents in cloned eCTD sequences.
                                                                                               [ Page 9 of the written specification concerning Directory/File structure
                                                                                               Sentence: “For the Centralised Procedure, the country subdirectory is always named "emea" and………..”]

  CR 20090909-05     Anne Mieke Reijnders,      EU M1 eCTD Specification v 1.4                 For both grouping and worksharing of variations page 19, 2nd paragraph, of EU Annex v1.4 states that:              Recommended on CR form: Text should be 'When submitting a grouping or                     Accepted referred to EMA business           When M1 specification   Agree. Remove word 'copied' and include             TIGes/EMA rapporteur     Yes
                     eCTD Consultancy                                                          “The ICH eCTD v3.x specification only allows the submissions of information relating to a single marketing         worksharing of variations,                                                                team                                        Annex 1.4 is updated    wording as proposed in EU M1 specification
                                                                                               authorisation. Therefore, when submitting a grouping or worksharing of variations, the eCTD submissions            eCTD submissions must be provided per marketing authorisation'.                           7/2010 - Follow-up with EMA business
                                                                                               must be copied per marketing authorisation.”                                                                                                                                                                 group [G. Isakkson]
                                                                                                                                                                                                                                                                                                            9/2010 - Owner of Module 1
                                                                                               Could you rephrase “copied” because depending on the individual product lifecycle different operation                                                                                                        specification is TIGes with EMA as
                                                                                               attributes, sequence numbers may be used.                                                                                                                                                                    rapporteur
                                                                                                                                                                                                                                                                                                            2/2011 - On hold per EMA




  CR 20090909-08     Hans van Bruggen,          EU M1 eCTD Specification v 1.4                 Page 10 of the written specification concerning File naming convention                                             Recommended on CR form: The naming convention is to be split for those                    Accepted                                    When M1 specification   Clarify in next minor version                       TIGes/EMA rapporteur     Yes
                     eCTDConsultancy B.V.                                                      Paragraph: File names in Module 1 have the general structure CC-FIXED-VAR.EXT, where CC is a                       documents pertaining to country-specific items and those not.                             7/2010 - Follow-up with EMA business        is updated
                                                                                               country code used in some CTD modules, FIXED is a defined component of the filename based on the CTD                                                                                                         group [G. Isakkson]
                                                                                               section and VAR is an additional optional variable component. EXT represents the file extension.                   Discussed in subgroup 20091210. Agreed. For implementation in next minor version          9/2010 - Owner of Module 1
                                                                                               Components are separated by a hyphen (except the dot for the file extension). No hyphens or spaces should          (specification only), for clarification.                                                  specification is TIGes with EMA as
                                                                                               be used within each component.                                                                                                                                                                               rapporteur
                                                                                               The naming convention is to be split for those documents pertaining to country-specific items (Sections 1.0;                                                                                                 2/2011 - On hold per EMA
                                                                                               1.2; 1.3 and 1.additional) and those not (1.4; 1.5; 1.6; 1.7; 1.8; 1.9; 1.10 and 1.responses). Note that for
                                                                                               1.responses a separate Change request has been written and submitted.
                                                                                               [Page 10 of the written specification concerning File naming convention]



  CR 20090909-10     Anne Mieke Reijnders,      EU M1 eCTD Specification v 1.4                 The comment describes a different instruction for MRP and DCP. What is the reason for this? Both MRP               Recommended on CR form: Depending on the reason, update the text by an                    Accepted                                    When M1 specification   Revise EU M1 spec to remove references to           TIGes/EMA rapporteur     Yes
                     eCTD Consultancy                                                          and DCP have a common and a national phase..                                                                       unambiguous description.                                                                  7/2010 - Follow-up with EMA business        is updated              procedures in the use of the common directory.
                                                                                               [page 21 comment # 8]                                                                                                                                                                                        group [G. Isakkson]                                                 Also review the wording alongside the
                                                                                                                                                                                                                  Discussed in subgroup 20091210. It is accepted that there is a need for clarification     11/2010 - transitioned to T. Mauer                                  pictures on p.8 under heading 'Decentralised
                                                                                                                                                                                                                  in the EU M1 v1.4 specification. The guidance on the use of the common directory          2/2011 - On hold per EMA                                            Procedure Directory Structure.'
                                                                                                                                                                                                                  should not include references to specific procedures.

    CR 20090922      Remco Munnik, Sandoz       EU M1 eCTD Specification v 1.4                 In version 1.4 of the Module 1 specifications, for the element “applicant” the following sentence has been         Discussed at TIGes/NtA Interlinking Meeting 20/10:                                        Accepted                                    When M1 specification   Make amendment to EU M1 specification               TIGes/EMA rapporteur     Yes
                                                                                               included for worksharing:                                                                                          Agreement to remove the sentence from the specification.                                  7/2010 - Follow-up with EMA business        is updated
                                                                                               For „worksharing‟ procedures, this should correspond to the applicant designated for the worksharing                                                                                                         group [G. Isakkson]
                                                                                               submission (and not all individual marketing authorisation holders for each product concerned).                                                                                                              9/2010 - Owner of Module 1
                                                                                                                                                                                                                                                                                                            specification is TIGes with EMA as
                                                                                               The inclusion of this “requirement” would lead to the fact that for a worksharing procedure, the company                                                                                                     rapporteur
                                                                                               that submits the eCTD application, must change the country specific envelope information every time.                                                                                                         2/2011 - On hold per EMA

                                                                                               Proposal of this CR is to remove this sentence from the specification.




    CR 20091203      Claire Holmes, EMEA        EU M1 eCTD Specification v 1.4                 New visual identity (new logo etc.) from 8 Dec on.                                                                 Content from a specific folder 'emea' also still needs to relate to new folder 'ema' -    Accepted                                    When M1 specification   Strategy for standards and specifications to be     TIGes/EMA rapporteur     Yes - Major revision
                                                                                               Still the European Medicines Agency, but no longer „the EMEA‟ – and not „the EMA‟ either. In future the            could be a tool change. What is the expected time frame for these changes? Need to        7/2010 - Follow-up with EMA Business        is updated to major     defined by EMEA. Specification changes only
                                                                                               fullname or 'the Agency' will be used.                                                                             look at all standards and systems.                                                        Group [G. Isakkson]                         version, DTD            could be implemented in a next minor version of
                                                                                               New „ema.europa.eu‟ address for website and e-mails from 8 December 2009: all Agency website and e-                                                                                                          9/2010 - Owner of Module 1                                          the EU M1 specification.
                                                                                               mail addresses will change from „emea.europa.eu‟ to „ema.europa.eu‟.                                                                                                                                         specification is TIGes with EMA as                                  9/2010 - Also needs DTD revision
                                                                                               From that date onwards, the address of the public website will be www.ema.europa.eu and e-mail addresses                                                                                                     rapporteur
                                                                                               will take the form name.surname@ema.europa.eu.                                                                                                                                                               2/2011 - On hold per EMA

                                                                                               Should this change be reflected in the EU M1 specification? Or is there no need as it seems the acronym
                                                                                               „EMA‟ will not be used?

    CR 20091204      Alastair Nixon GSK         eCTD BPG                                       The current eCTD BPG for MRP/DCP describes 2 different approaches for eCTD: the parallel national                  Ashley Birch: I do wonder whether anyone has actually used the PN Model - if not,         Accepted - refer to Interlinking Group      Nov-10                  CMD(h) to announce this in a press release in       Interlinking Group       No
                                                                                               model and the comprehensive model. In the section describing the parallel national model, it states,               there could in fact be no need for transition guidance, simply the removal of the PN      7/2010 - Follow-up with Interlinking                                November.
                                                                                               “Applicants should transition to the use of the „comprehensive‟ model at the earliest opportunity”. However,       option. If guidance is however necessary, then I think we would definitely need more      Group
                                                                                               the document does not describe how to do this. In reality, this will not be straightforward, and it is             detail on how to create a 'consolidated baseline'. It's not clear to me how this would    10/2010 - Interlinking Group - Agreed
                                                                                               suggested that, in addition to providing guidance, the parallel national model is removed as an option from        be done across many countries, unless it were preceded by individual NCA                  to withdraw the option of the parallel
                                                                                               now on.                                                                                                            sequences that deleted all previous content. If this were not done, and all the content   national model.
                                                                                                                                                                                                                  effectively baselined (resubmitted) in the subsequent consolidation sequence, then it     Interlinking
                                                                                                                                                                                                                  would be impossible to use an operator on an older document as it would potentially       2/2011: Agreed Announcement
                                                                                                                                                                                                                  appear in different sequences in different countries.                                     expected this week. If done close the
                                                                                                                                                                                                                  7/2010 - eCTD TG recommends low priority                                                  CR at the next CCB meeting.
                                                                                                                                                                                                                  10/2010 - Interlinking agreed on following:                                               3/2011 - TIGes Report from the Chair
                                                                                                                                                                                                                  CR is accepted. Interlinking group is of the opinion that the national parallel model     indicated the press release was done;
                                                                                                                                                                                                                  should not be used in future and proposes that in the next update of the Best Practise    thus this is completed.
                                                                                                                                                                                                                  Guide the model will be removed.
                                                                                                                                                                                                                  Proposal is that CMD(h) will publish a press-release in which it will be announced
                                                                                                                                                                                                                  that the national parallel
                                                                                                                                                                                                                  model is to be withdrawn. Any applicant that
                                                                                                                                                                                                                  used this model is requested to switch to the
                                                                                                                                                                                                                  comprehensive model within a period of 3 months.
                                                                                                                                                                                                                  NCA's will not accept any eCTD's that comply with the
                                                                                                                                                                                                                  national parallel model after the transition phase.
                                                                                                                                                                                                                  In case the applicant has questions on the switch
                                                                                                                                                                                                                  between different models, they should contact the
                                                                                                                                                                                                                  reference authority/RMS.
                                                                                                                                                                                                                  Should be forwarded to Karin Gröndahl




    CR 20091210      Geoff Williams, Roche      EU M1 eCTD Specification v 1.4                 The submission type “Withdrawal” in the EU Module 1 envelope is defined in the specification with two              Discussed in CR subgroup 20091210. Agreed to clarify in spec.                             Accepted - refer to Interlinking Group      11/16/2010 for Q&A      Finalise Q&A 27                                     TIGes/EMA rapporteur &   Yes
                                                                                               different meanings. We believe the usage may be unclear and propose some changes                                   10/2010 - Interlinking agreed on following :                                              7/2010 - Follow-up with Interlinking        When M1 specification                                                       Interlinking Group
                                                                                                                                                                                                                  CR is accepted.                                                                           Group                                       is updated
                                                                                                                                                                                                                  The submission type “Withdrawal” is only to be used for the withdrawal of a               10/2010 - Q&A 27 to be discussed at
                                                                                                                                                                                                                  Marketing Authorisation.                                                                  Interlinking in November
                                                                                                                                                                                                                  Geoff Williams to draft a Q&A on this topic. Q&A draft for discussion in November         2/2011 - M1 spec revision on hold per
                                                                                                                                                                                                                  Interlinking.                                                                             EMA


    CR 20091211      Claire Holmes, EMEA        EU M1 eCTD Specification v 1.4                 Term 'Periodic Report' should be removed from the EU M1 v1.4 specification as it can be confused with the          Discussed by Subgroup 20091210                                                            Accepted                                    When M1 specification   Remove term 'Periodic Report' from EU M1            TIGes/EMA rapporteur     Yes
                                                                                               Annual Report. CR arises from discussions on rejected CR 20090909.                                                 7/2010 - Changes need to go beyond EU M1 v 1.4.1; needs to be next minor version,         7/2010 - Follow-up with EMA Business        is updated              specification - update in next minor version
                                                                                                                                                                                                                  i.e. v 1.5                                                                                Group [G. Isakkson]
                                                                                                                                                                                                                                                                                                            9/2010 - Owner of Module 1
                                                                                                                                                                                                                                                                                                            specification is TIGes with EMA as
                                                                                                                                                                                                                                                                                                            rapporteur
                                                                                                                                                                                                                                                                                                            2/2011 - On hold per EMA



    CR 20091217      Danilo Steblaj, Slovenia   EU M1 eCTD Specification v 1.4                 The name of the Agency for Medicinal Products and Medical Devices of the Republic of Slovenia changed              Discussed by trial CCB 20100517                                                           Accepted - referred to Interlinking         When M1 specification   Change Agency name                                  TIGes/EMA rapporteur     Yes
                                                                                               from Agency for Medicinal Products and Medical Devices to current name in 2007. The document " EU                  7/2010 - Wider change assessment required. EUTCT, eAF? eCTD. Would need                   Group 17 May 2010 for implementation        is updated
                                                                                               eCTD module 1 specification v1.4" has still the old name "Agencija za zdravila in medicinske pripmocke"            to be next minor version. However we need a way in which the agency names can be          7/2010 - Follow-up with Interlinking
                                                                                               on page 39. The name should be changed to current name "Agency for Medicinal Products and Medical                  updated without major impact. ICH NMV?                                                    Group
                                                                                               Devices of the Republic of Slovenia".                                                                              10/2010 - Interlinking agreed on following :                                              9/2010 - Owner of Module 1
                                                                                                                                                                                                                  CR is accepted and issue should be solved in next update of the specification.            specification is TIGes with EMA as
                                                                                                                                                                                                                  However this CR should be referred to owner of the M1 specification (EMA).                rapporteur
                                                                                                                                                                                                                  Interlinking to inform Change Control Board (CCB) about this.                             10/2010 - CR should be sent to owner
                                                                                                                                                                                                                                                                                                            of M1 specification.
                                                                                                                                                                                                                                                                                                            2/2011 - On hold per EMA

  CR 20100128-01     Anita Anand Phadnis,       eCTD MRP/DCP Tracking Table                    On occasions a CMS is withdrawn during MRP or RUP. In a Word-based version of the tracking table it is             Discussed by trial CCB 20100517                                                           Accepted - referred to Interlinking         Mar-11                  Incorporate change to allow the withdrawal of a     Interlinking Group       No
                     Educe Solutions            specification v1.0, May 2008                   feasible to identity within the table that an CMS has been withdrawn. However, in an XML-based table the           7/2010 - Agreed by Interlinking - awaiting EMA allocation of resource to redevelop        Group 17 May 2010                                                   CMS in release plan for next version of XML-
                                                MRP/DCP eCTD Best Practice v1.0                specification does not easily support the withdrawal of a CMS.                                                     the spec for the XML table.                                                               7/2010 - Follow-up with EMA Business                                based tracking table
                                                                                                                                                                                                                  10/2010 - Interlinking agreed on following: CR is accepted.                               Group [G. Isakkson]
                                                                                                                                                                                                                  Further discussion in Interlinking is required on this topic. Especially on the           9/2010 - Needs follow up by Interlinking
                                                                                                                                                                                                                  situation of withdrawing a MS and later on re-entering of the same MS in the              10/2010 - Discussion in Interlinking
                                                                                                                                                                                                                  procedure.                                                                                required
                                                                                                                                                                                                                                                                                                            Interlinking 2/2011: Work in
                                                                                                                                                                                                                                                                                                            Progress. Expect to finalise at 3/2011
                                                                                                                                                                                                                                                                                                            meeting


    CR 20100408      Leigh Sandwell, Pfizer     EU M1 eCTD Specification v 1.4                 The two entries for Hungary in the EU eCTD Module 1 v1.4 stylesheet have mistakenly been swapped                   Discussed by trial CCB 2010 May                                                           Accepted - referred to Interlinking         When M1 specification   Correct the stylesheet to reference the correct     TIGes/EMA rapporteur     Yes
                                                                                               around so that the incorrect agency information is displayed in the stylesheet view; Institute also is             10/2010 - Interlinking agreed on following :                                              Group 17 May 2010 for review at June        is updated              agency names and fix the spelling mistake
                                                                                               misspelled in this chain                                                                                           CR is accepted and issue should be solved in next update of the specification.            meeting
                                                                                                                                                                                                                  However, this CR should be referred to owner of the M1 specification (EMA).               7/2010 - Interlinking Group needs to
                                                                                                                                                                                                                  Interlinking to inform Change Control Board (CCB) about this.                             give this the priority and implementation
                                                                                                                                                                                                                                                                                                            strategy, next minor version?
                                                                                                                                                                                                                                                                                                            10/2010 - Owner of Module 1
                                                                                                                                                                                                                                                                                                            specification is TIGes with EMA as
                                                                                                                                                                                                                                                                                                            rapporteur
                                                                                                                                                                                                                                                                                                            2/2011 - On hold per EMA

  CR 20100607-02     Sandra Taylor, J&J         EURS is Yours software used at agencies        An MRP eCTD was submitted to 28 EU countries. 9 countries were provided with country-specific                      Request copies of validation reports from requestor for more clarity.                     9/2010 - Accepted, referred to                                      Harmonisation Group to assess specifics of          Interlinking Group       No
                                                Feb 2010 (2.8.1 SP1?)                          application forms. For the remaining countries, a single form was provided that applied to all 19. For the 19                                                                                                Harmonisation Group                                                 situation against the specification and
                                                                                               countries, a single content file “uk-form.pdf” was provided in 0000\m1\eu\12-form\uk and this was                                                                                                            2/2011 - Harmonisation Group asked to                               validation criteria in order to determine whether
                                                                                               referenced by 19 XML leaves each associated with a different <specific> country attribute. This approach                                                                                                     pass this to Interlinking                                           software revisions are needed or these
                                                                                               is in line with the ICH eCTD Specification where it states that “Users of the eCTD Specification are                                                                                                                                                                             documents need to be more clear (or both).
                                                                                               encouraged to provide files once in a sequence and provide as m     any leaf elements referencing that file as
                                                                                               necessary. The location of the file is not critical and should only be included once in an appropriate place
                                                                                               in the folder structure” .

                                                                                               Note that the 0000\m1\eu\12-form\common folder or “common-form.pdf” filename was not used because
                                                                                               “common” identifies content potentially applicable to all EU countries, which was not the case in this
                                                                                               situation.

                                                                                               Agencies provided feedback that EURS is Yours gave a validation warning category B No. 35 (EURS is
                                                                                               Yours Validation Report, “Some file and folder names
                                                                                               do not match the EU M1.4 naming convention”, Validation Criteria v2.1: “EU M1.3
                                                                                               file name convention is followed”).

                                                                                               This is an incorrect validation result because the EU filenaming convention
                                                                                               “CC-FIXED-VAR.EXT” was followed. There are no checks defined in the EU eCTD
                                                                                               Validation Criteria that require leaf elements associated with a <specific> country code
                                                                                               to reference a file with the same country code in the filename.




    CR 20100805      Alastair Nixon GSK         EU eCTD validation process, SOP/H/3009         There appears to be no documentation describing the technical validation process for eCTD dossiers, in             CCB fully agreed with the need to address this. There is benefit to both the Agency       CCB 9/2010 - Referred to                                            While addressing the update to the validation       Interlinking Group       No
                                                [WIN/H/3251 AND WIN/PDM/1702 (eCTD             particular what happens in the event of validation failure. If dossier contents are incorrect, then the            to not have to reinitiate the validation process and for the applicant to avoid           Harmonisation Group                                                 criteria, it would be beneficial to give a window
                                                technical validation)] Effective date 21 JUN   applicant is given time to fix the issue with a subsequent sequence. However, if the original sequence is          encountering a delay in review clock initiation.                                          1/2011 - Harmonisation Group asked to                               of time to submit a corrected sequence.
                                                10                                             technically incorrect, there are no written provisions for the applicant to provide a replacement. If the                                                                                                    pass this to the Interlinking Group
                                                                                               regulator does not process the validation and upload promptly following receipt then time for correction of                                                                                                  1/2011 - Interlinking accepted
                                                                                               any technical error is lost which could result in a procedure being significantly delayed. Many category A
                                                                                               errors in the eCTD can be caused by relatively minor problems – for example, an extra file on the CD
                                                                                               (unreferenced content, check 45, cat A), one file name longer than 64 char, (check 31, Cat A), missing title
                                                                                               in delete leaf, (check 12, Cat A). In addition, whilst industry is still using hard media to provide the eCTD to
                                                                                               the agencies, and since the EMA only requires one copy of the media, any damage to the CD in transit
                                                                                               could also delay a procedure. These kinds of errors
                                                                                               can be fixed very quickly, but at present there is no documented mechanism for
                                                                                               provision of time to the applicant to fix and provide a corrected sequence. Clearly,
                                                                                               all applicants aim to submit 100% valid eCTDs 100% of the time, but errors can
                                                                                               occur, and the lack of any process to fix errors could result in unnecessary delays
                                                                                               in registering new medicines.




    CR 20100920      Geoff Williams, EFPIA      EMA Implementation of Electronic-Only          Information is currently requested to be provided at up to 8 different milestones during an MAA regulatory         10/2010 - CCB fully agreed with this recommendation                                       CCB 9/2010 - Accepted, referred to          Next major release                                                          EMA                      No
                     eCTD Topic Group           Submission and eCTD Submission:                activity as an eCTD submission sequence in the Centralised Procedure. This includes the provision of                                                                                                         EMA
                                                Questions and Answers Relating to              labeling information, as appropriate to the milestone, within the procedure. The labeling information is                                                                                                     2/2011 - on hold
                                                Practical and Technical Aspects of the         already sent via Eudralink to ensure that applicants meet the tight procedure timelines that would currently
                                                Implementation & Guidance for Industry on      be difficult to achieve with the creation and dispatch of an eCTD sequence. The additional requirement to
                                                Providing Regulatory Information in            then follow up with an eCTD sequence creates additional unnecessary work for applicants and is not
                                                Electronic Format: eCTD electronic             necessary to enable the review of the dossier.
                                                Submissions
                                                                                                                                                                                                                                                                                                EU eSub Change Requests

Pink = rejected;
Green = Completed;
Blue = New
         #                 Requestor                       Specification                                                                      Description                                                                                             Comments                                               Status                                    Due Date                   Action                                                Group W here Action is   Implement in EU M1 Revision
                                                            Component                                                                                                                                                                                                                                                                                  [where applicable]                                                               Sitting
    CR 20101020      Geoff Williams, Roche      EU M1 eCTD Specification v 1.4              The EU Module 1 eCTD specification identifies the acceptable file formats for inclusion within Module 1 of          We recommend removing any reference to RTF as an acceptable file format in the               11/2010 - Accepted, referred to           When M1 specification      Remove any reference to RTF as an                     TIGes/EMA rapporteur &   Yes
                                                                                            a European eCTD. This information is in the section Regional File Formats (beginning the bottom of page             EU Module 1 eCTD specification at the next update to the specification document.             rapporteur of M1 specification            is updated                 acceptable file format in the EU Module 1             Interlinking Group
                                                                                            5) and summarised in Table 1.                                                                                                                                                                                    2/2011 - On hold per EMA                                             eCTD specification at the next update to the
                                                                                                                                                                                                                If an update to the eCTD specification is some time away, we recommend issuing a                                                                                  specification document. If an update to the
                                                                                            “Acceptable for inclusion in the eCTD” has generally meant that the file formats are acceptable for a leaf          Q&A in the short term to announce this change.                                                                                                                    specification is some time away then a Q&A to
                                                                                            within the eCTD to reference using the xlink:href attribute. Since the original publication of this table in                                                                                                                                                                          meet the interim need should be written.
                                                                                            version 1.0, best practice has turned into guidance and the EU now only accepts RTF and MS Word files in
                                                                                            a separate “working documents” folder. This fact is acknowledged in passing in the EU Module 1 eCTD                                                                                                                                                                                   11/2010 - Does assignment of Q&A draft need
                                                                                            specification, v1.4, which says:                                                                                                                                                                                                                                                      to be made?

                                                                                            “Although RTF is an accepted eCTD file format, it is also generally accepted that RTF files should also
                                                                                            only be provided in addition to PDF versions, and that they should also not be referenced in the eCTD
                                                                                            backbone.”

                                                                                            Furthermore, the information about acceptable file formats for the eCTD is also used by the NeeS
                                                                                            specification and is the basis for validation criteria about the acceptable file formats for both eCTD and
                                                                                            NeeS.

                                                                                            The inclusion of RTF is one difference between the ICH eCTD and the EU Module 1 eCTD. Given that the
                                                                                            RTF files should not be referenced from the XML backbone we feel it is now time to amend the specification
                                                                                            and remove RTF as an acceptable format.

                                                                                            This issue was discussed by the TIGes Harmonisation Group while drafting the new eCTD and NeeS
                                                                                            validation criteria and has their endorsement.
  CR 20101022-01     Leigh Sandwell, Pfizer     EU M1 eCTD Specification v 1.4 and HMA      The EU eCTD Module 1 v1.4 Specification document identifies the Czech Republic agency as:                           11/2010 - CCB accepted; include in M1 specification update                                   11/2010 - Accepted, referred to           When M1 specification      Correct the stylesheet and HMA website to             TIGes/EMA rapporteur     Yes
                                                website                                     Czech Rep - State Institute for Drug Control                                                                                                                                                                     rapporteur of M1 specification            and HMA website are        reference the correct agency name.
                                                                                            The stylesheet file (eu-regional.xsl) for EU eCTD Module 1 v1.4 identifies it as:                                                                                                                                                                          updated
                                                                                            Czech Rep - State Institut für Drug Control
                                                                                            Feedback from our Czech Republic affiliate is that the agency name should be State Institute for Drug
                                                                                            Control.
                                                                                            This is confirmed by the SUKL website which uses the following Czech and English versions of the agency
                                                                                            name respectively:
                                                                                            Státní ústav pro kontrolu léčiv
                                                                                            State Institute for Drug Control
                                                                                            These names are listed correctly on the EMA website, but the name of the agency also appears to be the
                                                                                            incorrect version on the HMA website:
                                                                                            http://www.hma.eu/index.php?id=11&showctr=16

  CR 20101022-02     Leigh Sandwell, Pfizer     EU M1 eCTD Specification v 1.4              In the September minutes from the CHMP meeting there was a Procedural Announcement on the                           11/2010 - CCB accepted; include in M1 specification update                                   11/2010 - Accepted, referred to           When M1 specification      An interim Q&A should be provided as soon as          TIGes/EMA rapporteur &   Yes
                                                                                            requirement to submit the Letter of Undertakings (LoU) as an eCTD sequence:                                                                                                                                      rapporteur of M1 specification            is updated                 possible pending any updates to the guidance.         Interlinking Group
                                                                                            The European Medicines Agency is repeatedly receiving the Letter of Undertakings (LoU) in paper                                                                                                                  2/2011 - On hold per EMA
                                                                                            format, however:
                                                                                            “Any submissions made in the context of a Centralised Application Procedure and the subsequent
                                                                                            maintenance of the lifecycle of the application (e.g. initial applications (including ASMF, PMF),
                                                                                            supplementary information, variations, renew als, Follow -Up Measures (FUMs), Periodic Safety Update
                                                                                            Reports (PSURs), Notifications etc) are covered by eCTD requirement “
                                                                                            Applicants are advised that if due to short procedural timelines the LoU is submitted within a Eudralink
                                                                                            message, they are obliged to follow this up with an eCTD sequence.
                                                                                            From 15 October 2010 any paper submission of Letter of Undertaking (as normal correspondence) will
                                                                                            therefore not be considered as valid submission.
                                                                                            There is currently no specific Submission Type for a Letter of Undertaking eCTD sequence in the EU
                                                                                            eCTD Module 1 v1.4 Specification. Also, a Letter of Undertaking
                                                                                            may have a relationship to previously submitted information.
                                                                                            Clarification is required in the eCTD guidance to define what Submission Type
                                                                                            should be selected for a Letter of Undertaking eCTD sequence and whether a
                                                                                            related sequence is required if there is a relationship to a previously provided eCTD
                                                                                            sequence. The location of the LoU in an eCTD sequence should also be clearly
                                                                                            defined.



    CR 20101122      Stephen W Cook,            Volume 2B Notice to Applicants, Medicinal   The lack of more detailed guidance on handling variations (irrespective of the                                      12/2010 - pre-CCB EFPIA eCTD TG - can be addressed with M1 specification                     12/2010 - Accepted, referred to           When M1 specification      To be addressed in the M1 specification               TIGes/EMA rapporteur     Yes
                     GlaxoSmithKline            products for human use, Presentation and    new variation regulation) causes divergent interpretation within the EMA and to                                     revision [specifically Appendix 2, Row 8 plus reference from Row 71 back to Row 8];          rapporteur of M1 specification; request   is updated                 revision as well as further detail in the variation
                     Biologicals s.a.           format of the dossier, Common Technical     a lesser extent across agencies. Though it is limited in this case to a single                                      change could state to see ICH CTD guidance and Q&A [without specific version                 consultation from Interlinking group                                 guidance re specific types of supportive
                                                Document (CTD), Module 1, 1.2 Application   document, it has led to unnecessary validation rejections followed by                                               reference so easier to maintain].                                                                                                                                 documents - bring to CMD(h)
                                                Form                                        administrative burdens. The document concerns supportive document, not to be                                        CCB - new guidance needs to clearly define what is 'supportive' vs. what will have
                                                                                            submitted in Module 2-5 and therefore annexed to the application form. The                                          lifecycle and needs to be readily available in the current view for critical review of the
                                                                                            handling of variation documentation needs to be further explained in the Notice to                                  application
                                                                                            Applicants.
    CR 20101129      Geoff Williams, Roche,  EU M1 eCTD Specification v 1.4                 The EU Module 1 specification specifically states that hyphens are not allowed in the variable (VAR) part of        1/2011 - Update the specification document in the two sections identified to remove          1/2011 - Accepted, referred to            When M1 specification      Revise wording in the 2 sections identified to        TIGes/EMA rapporteur     Yes
                     for Harmonisation Group                                                file names on page 10 (File Naming Convention, last sentence of the first paragraph) and on page 21 (item           the prohibition and specifically allow the use of hyphens in the variable portion of the     rapporteur of M1 specification            is updated                 remove the prohibition and allow the use of
                                                                                            8 of Appendix 2, comments section).                                                                                 file name. Harmonisation Group suggests that this should be stated so as to make             2/2011 - On hold per EMA                                             hyphens in the variable portion of the file name.
                                                                                            No one on the TIGes Harmonisation Group can recall why this prohibition was introduced. Nor can we find             the change clear to readers of the specification.
                                                                                            any good reason to continue to to prohibit the use of hyphens.                                                      CCB: Suggest that when the M1 spec is revised that mention of path length
                                                                                            On the contrary, hyphens are the only way of helping provide meaning to the variable part because spaces            considerations should be made when deciding whether hyphens are needed or not.
                                                                                            are not allowed.                                                                                                    The CR mentions M2-5 in the Summary. This is outside of the regional M1
                                                                                            The TIGes Harmonisation Group have discussed this thoroughly and feel that allowing hyphens in the                  specification and already addressed in the ICH eCTD specification.
                                                                                            variable part of the file name is beneficial. In the proposed new eCTD criteria (published for public
                                                                                            consultation in November 2010) this change was proposed and has not met any resistance from tool
                                                                                            vendors, applicants or agencies.

    CR 20101203      Cynthia Piccirillo, BMS,   EU M1 eCTD Specification v 1.4                                                                                                                                  12/2010 - In alignment with the CR process, a CR has been prepared to recommend              12/2010 - Accepted, referred to           When M1 specification      To revise the M1 specification & stylesheet to        TIGes/EMA rapporteur     Yes
                     for EMA CCB                                                            There are currently at least 17 change requests, and possibly 20 change requests, that could be completed           a minor level revision of the M1 specification & stylesheet to address all related           rapporteur of M1 specification            & stylesheet are updated   address all CRs that can be addressed with a
                                                                                            through a minor level revision of the EU Module 1 specification and stylesheet. The next major revision is          active CRs and work toward retirement of all Q&As                                            2/2011 - On hold per EMA                                             minor level revision
                                                                                            not anticipated until 2013. In addition, all existing or drafted/planned Q&As could be retired as a result of
                                                                                            undertaking this activity. Therefore, the CCB believes a sufficient number of CRs have accumulated and it
                                                                                            is justified to assign an author(s) to undertake the M1 specification and stylesheet revisions.
    CR 20101214      Jaakko Hartikka, Finnish   EU M1 eCTD Specification v 1.4              The Agency name of Finland changed 1.11.2009 to “Finnish Medicines Agency”. In EU Module 1                          CCB 1/2011 - The name of the Agency can be changed in the forthcoming M1                     1/2011 - Accepted, referred to            When M1 specification      Change Agency name                                    TIGes/EMA rapporteur     Yes
                     Medicines Agency                                                       Specification Appendix 2.4 page 38 there is obsolete Agency name “National Agency for Medicines” and                specification revision, but the Agency code will have to wait until the next revision of     rapporteur of M1 specification            is updated
                                                                                            Agency code “FI-NAM”. The new proposed agency code is “FI-FIMEA”. They should be updated to the                     the DTD.                                                                                     2/2011 - On hold per EMA
                                                                                            documentation and to the related XML backbone files in eCTD EU M1.                                                  CCB agreed.

    CR 20110120      Remco Munnik, Sandoz       • Guidance for Industry on Providing        Currently it is not clear how to handle translations of SmPC, PL and label for variations. It is defined that for   Clarify in the guidance document that there is no need to include national                   CCB 3/2011- Accepted                                                 Ask Karin Grondahl who should receive the CR          CCB                      No
                                                Regulatory Information in Electronic        national finalisation phase of MRP/DCP national translations can be handled outside eCTD.                           translations in the eCTD folder structure.                                                                                                                        for CMD(h) to consider
                                                Format: Non-eCTD electronic Submissions     However for some variations, updated SmPC, PL and label should be attached. It is currently not clear if the        In case national translations are provided, these should be attached in the “working-
                                                (NeeS) for human medicinal products.        national translations of the English core SmPC, PL and label to be included in eCTD for variations.                 documents” folder and not in the eCTD folder.
                                                Version 2.0, March 2010                                                                                                                                         In order to provide clarity a Q&A document should be created and published until the
                                                • Guidance for Industry on Providing                                                                                                                            guidance document is updated.
                                                Regulatory Information in Electronic                                                                                                                            pre-CCB seems to be missing text. Also, the NeeS guidance seems to have the
                                                Format: eCTD electronic Submissions.                                                                                                                            needed text under paragraph 3.2; this text could be brought to the eCTD guidance
                                                Version 1.0, May 2009.
                                                • Existing Q&A “How to deal with National
                                                Translations of the Product Information?”



   CR 20110127-01    Cynthia Piccirillo, BMS    EU NeeS Guidance v 2.0, March 2010          A member company was requested to file a submission containing a PSUR document in NeeS format for                   CCB 2/2011 - The CCB agrees in concept that some revision is needed, the actual              CCB 2/2011 - Accepted, referred to the                               Requestor: Revise the guidance to remove the          Harmonisation Group      No
                     for EFPIA eCTD TG                                                      Finland. It is unclear where to place the PSUR document. In an eCTD submission this information would               revision should consider the following:                                                      Harmonisation Group                                                  text, “In these examples there are some “Not
                                                                                            be placed in section 5.3.6. In the NeeS guidance documents, section 5.3.6 is listed as Not Applicable. The          The TOC included in the NeeS guidance is only an illustration how the TOC should                                                                                  applicable” documents shown. “Not applicable”
                                                                                            guidance does not provide direction as to where this type of report should be placed. This scenario is also         be prepared. There are some “Not applicable” entries in the exam of the TOC
                                                                                                                                                                                                                                                                                     ple                                                                                          documents should not appear in the dossier
                                                                                            applicable to the following documents:                                                                              due to the fact that this probably only displays what would be included in a new MAA,                                                                             and nor should they be included in the TOCs.”,
                                                                                            Information for Generic, `Hybrid` or Bio-similar Applications                                                       i.e. a PSUR would not be included. But under section 2.2 Structure of Submissions it                                                                              and replace the various „Not Applicable‟
                                                                                            (Extended) Data/Market Exclusivity                                                                                  is clearly stated how the regulatory information must be structured and which rules                                                                               entries that are there with a sample of a link.
                                                                                            Exceptional Circumstances                                                                                           should be followed. This also applies to the other items listed in the CR. Thus the                                                                               CCB: See Comments
                                                                                            Conditional Marketing Authorisation                                                                                 guidance needs to be explicit that this is only an example and the CTD                                                                                            2/2011 Harmonisation Group: The group
                                                                                            Market Exclusivity                                                                                                  granularity/structure identifies where to include these other items, as applicable to a                                                                           agreed that the example in the NeeS guidance
                                                                                            Responses to Questions                                                                                              particular submission type.                                                                                                                                       could be clarified to avoid any confusion. It will
                                                                                            Additional Data                                                                                                     It may help to include additional examples for other types of submissions to further                                                                              be reflected as the guidance is updated
                                                                                            3.2.P.4:                                                                                                            illustrate scenarios.                                                                                                                                             (planned during Q1-2 2011).
                                                                                            Analytical Procedures                                                                                               Some of the items listed in the change request are not applicable since NeeS is no
                                                                                            Validation of Analytical Procedures                                                                                 longer accepted for the CP.
                                                                                            Justification of Specifications



  CR 20110214-01     Geoff Williams, Roche,  eCTD Validation Criteria, worksheet on         The ICH M4 document on Granularity allows for three options for the granularity in Module 2.3 (the Quality          The ICH M4 document on Granularity allows for three options for the granularity in           CCB 2/2011- Accepted - referred to        In the next minor update   The TIGes Harmonisation Group discussed               Harmonisation Group      No
                     for Harmonisation Group file/folder naming - eCTD: v3.0, Jan 2011      Overall Summary). The eCTD file naming provided in v3.2.2 of the ICH specification sets out the filenames           Module 2.3 (the Quality Overall Summary). The eCTD file naming provided in v3.2.2            Harmonisation Group                       to the eCTD validation     this matter on 11th Feb 2011 and proposed
                                             NeeS validation Criteria, worksheet on         for the middle level of granularity. The finer level of granularity can be accommodated by using the “-var”         of the ICH specification sets out the filenames for the middle level of granularity.                                                   criteria spreadsheet.      adding the filename qos-var.pdf as an option
                                             file/folder naming - eCTD: v3.0, Jan 2011      variable element on the end of the ICH filenames. However, there is no published filename to use for the            The finer level of granularity can be accommodated by using the “-var” variable                                                                                   OR to use the filenames already shown. The
                                                                                            coarser level of granularity (a single file for the whole of the QOS).                                              element on the end of the ICH filenames. However, there is no published filename to                                                                               screenshot shows the proposed layout
                                                                                                                                                                                                                use for the coarser level of granularity (a single file for the whole of the QOS).
                                                                                            The new NeeS validation criteria make the file names in Modules 1-3 mandatory (they are P/F tests).
                                                                                            Therefore, if the applicant chooses to submit a single file, there is no suitable filename value.                   The new NeeS validation criteria make the file names in Modules 1-3 mandatory
                                                                                                                                                                                                                (they are P/F tests). Therefore, if the applicant chooses to submit a single file, there
                                                                                                                                                                                                                is no suitable filename value.




  CR 20110214-02     Geoff Williams, Roche,  eCTD Validation Criteria, Item 10.1, eCTD:     The comment that has been made alongside the eCTD validation check 10.1 is not a logical result of the                                                                                                           CCB 2/2011- Accepted - referred to                                   The TIGes Harmonisation Group discussed               Harmonisation Group      No
                     for Harmonisation Group v3.0, Jan 2011                                 check.                                                                                                                                                                                                           Harmonisation Group                       In the next minor update                    th
                                                                                                                                                                                                                                                                                                                                                                                  this matter on 11 Feb 2011 and proposed
                                                                                                                                                                                                                                                                                                                                                       to the eCTD validation     deleting the comment.
                                                                                                                                                                                                                                                                                                                                                       criteria spreadsheet.
    CR 20110228      Remco Munnik, Sandoz       Guidance for Industry on Providing          In paper and NeeS format an applicant can built the submission at the headquarters for the common                   Harmonisation group should clarify how to handle national documentation.                     CCB 3/2011- Rejected                                                 Propose for discussion at TIGes as part of a          CCB
                                                Regulatory Information in Electronic        documentation and send this out to the Country Organisations (CO). The CO‟s s attach local                          In order to facilitate companies to incorporate eCTD fully, it would be proposed to                                                                               general topic on difficulties applicants are
                                                Format: eCTD electronic Submissions.        documentation (translations of cover letters, application forms, declarations, statements, proof of payments,       store any national declaration, statement, translation, etc in the “workingdocuments”                                                                             having with eCTD in the different procedures
                                                Version 1.0, May 2009.                      etc).                                                                                                               folder.
                                                                                            For eCTD it is required that all documentation is included in the eCTD.                                             CCB - Agree that there is difficulty in preparation, however this approach would
                                                                                            This means that for an eCTD the CO‟s have to send all national documentation to the headquarters where              create a loss of functionality of the eCTD structure with putting required documents
                                                                                            the eCTD is created.                                                                                                in the "workingdocuments" folder and potentially a greater burden on NCAs.
                                                                                            This is an additional and time-consuming step, which delays the submissions of eCTD‟s compared to
                                                                                            paper and NeeS.
                                                                                            In order to remove this additional step it should be allowed to submit all national documentation in the
                                                                                            “workingdocuments” folder.
                                                                                            This way the national NCA‟s still receive the documentation together with the eCTD, but the documentation
                                                                                            doesn‟t have to be included in the eCTD.
                                                                                            This would remove for an applicant one objection from business perspective to switch fully to eCTD.


   CR 20110309-01    Leigh Sandwell             EU eCTD Module 1 Specification              The Module 1 Specification allows for more than one Related Sequence, but only shows examples of one                Discussion in the Harmonisation subgroup on Related Sequences                                CCB 3/2011 - Accepted - referred to                                                                                        Harmonisation Group      Yes
                     Pfizer                                                                 Related Sequence being provided. It is generally expected that there is usually just one Related Sequence,                                                                                                       Harmonisation Group
                                                                                            but, from experience, there appears to be occasions where more than one Related Sequence should be
                                                                                            provided:
                                                                                            e.g. 1: There are two FUMs (sequence 0050 and sequence 0060) and a single response (sequence 0070)
                                                                                            is produced that relates to both FUMs.
                                                                                            e.g. 2: There are two parallel variations (sequence 0020 and sequence 0030) and there is a sequence
                                                                                            (0040) that brings the label up to date by including the changes made in both variations.
                                                                                            Clarification should also be given on the implications on the Envelope Metadata (for example if a labeling
                                                                                            consolidation sequence involved both a single and grouped variation, what would the metadata state) and
                                                                                            subsequent lifecycle sequences (for example what if there was a further sequence referring to just one of
                                                                                            the original sequences).



   CR 20110309-02    Leigh Sandwell             „CMDh Best Practice Guide on the use of     One of our products moved from separate National applications to the MRP after an Article 30 referral. The          Update the Best Practice Guide/Harmonised eCTD guidance to provide clarity on                CCB 3/2011 - Accepted - referred to                                                                                        Harmonisation Group      No
                     Pfizer                     eCTD in the MRP/DCP‟ Rev2, June 2010        National submissions were all in NeeS format except for two countries who had been receiving eCTD.                  what to do when there is a referral.                                                         Harmonisation Group for a position and
                                                and TIGes „Guidance for Industry on         These two countries are CMSs in the new MRP. Due to complications of moving this product to eCTD                    In the interim a Q&A should be produced.                                                     then owners of the respective
                                                Providing Regulatory Information in         (particularly within the required timelines), it was proposed that the MRP be submitted in NeeS format. As                                                                                                       guidances for possible revisions
                                                Electronic Format: eCTD electronic          the MRP has a new procedure number after the Article 30 alignment, it had been expected that there would
                                                Submissions‟ Version 1.0 May 2009           be no issue with the proposal to move to NeeS and the Article 30 referral itself was submitted in NeeS
                                                                                            format.

                                                                                            The proposal was agreed as acceptable to the RMS and one of the CMS that had previously received
                                                                                            eCTD, but the other CMS stated that an eCTD must be provided. After further discussion the other CMS
                                                                                            agreed that this could (on this occasion only) be submitted in NeeS format, but it was stated that products in
                                                                                            eCTD format will not be allowed to change to NeeS format in the future. Whilst we generally agree that
                                                                                            applicants should never change from eCTD to NeeS within a procedure, in the case outlined it seems
                                                                                            acceptable to be able to do this
                                                                                            as a new procedure number is assigned and there is no technical relationship between the
                                                                                            National submissions and MRP.

                                                                                            Clarification is required on whether it is acceptable to be able to provide NeeS for the eCTD
                                                                                            or whether one CMS can enforce the use of the eCTD for the whole procedure.
#                                Question                                                                                  Answer                                                      Approval        Text Included in EU M1 v1.4?         Include Text in EU M1
                                                                                                                                                                                         Date                                                     Revision?

10 Where can node extensions be used in a EU eCTD submission?       Node extensions may be used where additional navigation in the XML backbone is required. The                         Mar-2007   Partially                         YES
                                                                    primary place where they may be used is in Module 5 where a node extension for each study may be
    The question was generated by ICH change request 00560 and the useful so as to allow multiple files for a single study to be grouped together and separated distinctly
    response to ICH eCTD Question 28. This is recorded as EU Change from other studies. For Module 4 where there are multi-file reports this can also be useful. Other
    Request A010.                                                   places where they can be useful is in Module 1 to differentiate between PI documents provided in PDF
                                                                    and those provided in RTF/Word and in Module 5 to differentiate reports associated with a different
                                                                    dosing regimen for the same indication.

                                                                             However, the use of node extensions should be limited to those areas where it is critical and
                                                                             consideration should be given regarding the impact of the view for the reviewer since the inconsistent
                                                                             use of node extensions can lead to unanticipated effects in the cumulative view of a submission.




23 Lifecycle across sections                                                 Click on icon for Answer                                                                                               N/A
   This question was generated by EU Change Request CR-20090615



                                                                                                             Q&A 23.doc



24 In the EU Module v1.4 the related-sequence element in the envelope The inclusion of the optional country attribute was an error. This attribute had been removed from the           Oct-2009     NO                                YES
   can be declared with an optional country attribute. Should this be previous version of the specification.
   used?
   This question was generated by EU Change Request CR-20090820 There is no requirement for the applicants to use this attribute. Furthermore, tool vendors should not
                                                                      include this in their tools for creating EU Module 1 v1.4 as this was included in error.


25 The new EU M1 specification and eCTD validation rules place more          Click on icon for Answer                                                                                  Feb-10       N/A                               N/A
   emphasis on using the related sequence element in the eCTD
   correctly. However, although there are already some general
   guidelines available (Q&A #12 in the EU Change Request/Q&A
   Tracking Table), there is a need to provide more guidance,
   particularly related to different regulatory activities. Can additional                                   Q&A 25.doc
   guidance be provided?
   This question was generated by discussion at Feb 2010 Interlinking
   Group Meeting

26 Typically a baseline submission is filed as a single sequence for    Click on icon for Answer                                                                                       Feb-10       N/A                               N/A
   which the submission type „reformat‟ will be used. However, it is
   possible that a baseline can be submitted as multiple sequences,
   e.g one sequence for the baseline for Modules 4 and 5 followed later
   by one sequence for the baseline for Module 3. In such a
   circumstance what should the submission type of the second                                                Q&A 26.doc
   baseline be and should a Related Sequence be used for the second
   baseline?
   This question was generated by discussion at Feb 2010 Interlinking
   Group Meeting
27 The EU Module 1 Specification, v1.4 currently defines two uses for        The submission type „withdrawal‟ should only be used for the notification by the applicant to the         Feb-10       N/A                               N/A
   the submission type “withdrawal”. Should the submission type              regulator of the withdrawal of a marketing authorisation. It should not be used for the withdrawal of a
   „withdrawal‟ be used for both the notification of a withdrawal of a       variation, or parts of a grouped variation, during the assessment. In this circumstance the submission
   marketing authorisation and for the withdrawal of a variation             type to use is „supplemental-info‟.
   submission during assessment?
   This question was generated by discussion at Feb 2010 Interlinking
   Group Meeting
#                              Question                                                                 Answer   Approval     Text Included in EU M1 v1.4?         Include Text in EU M1
                                                                                                                   Date                                                  Revision?

28 The EU Module 1 specifications refers to the fact that “Filename for To be generated                                     N/A                              YES
   responses to questions composed by a fixed component “CC”, a
   fixed component “responses” and an optional variable component to
   be used if needed (e.g. be-responses.pdf)”
   This suggests that response documents are written per country in
   multi-country submissions. However in practise responses for a
   multi-country submission are regarded as common.
   Can clarification be provided as to how the country specific folders
   and file-naming should be used?

    This question was generated by EU Change Request CR-20090909-
    02.




29 With a paper submission there is the possibility of submitting      Under discussion for inclusion                       N/A
    a response to a question which may contain a proposal (e.g.
    a change to the specification) and at a later moment in time,
    when the answer is found to be acceptable by the regulators,
    the revised Module 3 content can be submitted.
    Is it with a submission in eCTD-format always expected that
    the Module 3 section is updated at the time of submitting the
    response or can this also be delayed until it is known that the
    response is acceptable?
    This question was generated by EU Change Request CR-
    20060627-03.
#   Question   Answer   Approval   Text Included in EU M1 v1.4?   Include Text in EU M1
                          Date                                          Revision?
                                                                                                                                                                                                                                      EU eCTD Specification Change Requests
 #         Requestor                  Specification                                                   Description                                                                              Comments                                     Status                  Action                                Group Where Action   Notes
                                       Component                                                                                                                                                                                                                                                          is Sitting
A001   generated by EU                                      What is the EU's position on the use of XML for the content of the submission instead of PDF          In line with the general principles of the ICH eCTD Specification         Approval date: 1.3.2007 closed
       Change Request                                       and/or RTF?                                                                                           Document, it is intended that XML will become the submission
       A001                                                                                                                                                       format for administrative forms and product information documents
                                                            This question was generated by EU Change Request A001                                                 as they contain structured data. The long term goal of this
                                                                                                                                                                  development is the normalisation of data in Module 1. As the XML
                                                                                                                                                                  documents become available for practical implementation, they will
                                                                                                                                                                  be introduced into Module 1 and the current file formats may be
                                                                                                                                                                  replaced after a transition period.
A002   generated by EU     eCTD EU Module 1 Specification   Can further guidance be given on the acceptable formats for product information in the eCTD?          With respect to product information (PI) documents, the currently         Approval date: 1.3.2007 closed                                N/A                  Already addressed in EU M1 specification - no
       Change Request                                                                                                                                             acceptable file formats are indicated in the EU Module 1                                                                                                     need to make any change.
       A002                                                                                                                                                       specification. When generating product information files for the
                                                                                                                                                                  Centralised, Mutual recognition and Decentralised Procedures,
                                                                                                                                                                  QRD templates as issued by the EMEA should be used. For
                                                                                                                                                                  National Procedures, refer to national guidance. The EU will be
                                                                                                                                                                  moving into the direction of an XML approach for the exchange of
                                                                                                                                                                  product information as part of the Product Information Management
                                                                                                                                                                  (PIM) project which is currently being implemntated in the
                                                                                                                                                                  Centralised Procedure. For additional details on the PIM project,
                                                                                                                                                                  see: http://pim.emea.europa.eu
A003   generated by EU     eCTD EU Module 1 Specification   Is the submission of application forms as XML documents acceptable?                                   It is the intention of the EU to provide XML standards for application    Approval date: 1.3.2007 closed                                N/A                  Update wording of Q&A #3 to reflect current
       Change Request                                                                                                                                             forms. The specifications for new and variations forms have been                                                                                             situation regarding development of application
       A003                                                                                                                                                       issued and can be accessed at                                                                                                                                form standard.
                                                                                                                                                                  http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev2.ht
                                                                                                                                                                  m. An electronic version of the renewals form is currently under                                                                                             LD: Need to pay attention to the lack of
                                                                                                                                                                  development. Refer to national guidance regarding the applicability                                                                                          synchronisation between eAF and paper
                                                                                                                                                                  of the XML Application Forms.                                                                                                                                versions. The last version of eAF XML is Feb
                                                                                                                                                                                                                                                                                                                               2007 while PDF/Word forms are:
                                                                                                                                                                                                                                                                                                                               - New has changed (May'08)
                                                                                                                                                                                                                                                                                                                               - Var has changed (May'08)
                                                                                                                                                                                                                                                                                                                               - Renewal is ok (Feb'07)
A007   generated by EU     eCTD EU Module 1 Specification   I am trying to understand the complete scope of what submissions are to be                            The EU Module 1 specification defines the submission types that           Approval date: 1.3.2007 closed                                N/A                  Update wording of Q&A #7 to refer to current
       Change Request                                       required as CTD/e-CTD submissions in the EU.                                                          are part of the eCTD (V1.2.1, p10). All of these submission types                                                                                            version of EU M1 spec (the Q&A currently
       A007                                                 From reading some background on the topic, I think the scope may include:                             are covered, including Follow-up Measures and PSUR                                                                                                           references v1.2.1).
                                                            - all new applications                                                                                submissions.
                                                            - all variations
                                                            - all response documents (MRP and CP response documents)
                                                            - all renewals
                                                            but does not include
                                                            - submissions of data as part of a FUM but which is not a variation
                                                            - PSUR submissions
                                                            Can you please confirm/correct this understanding.




A008                       eCTD EU Module 1 Specification   I am seeking information on the structure of the eCTD response to list of questions dossier. In the   The May 2006 version of the Notice to Applicants                          Approval date: 1.3.2007 closed                                N/A                  Update wording of Q&A #8 to refer to current
                                                            eCTD EU module 1 specifications v1.0, it is stated that responses to questions can be included        (http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-                                                                                                version of EU M1 spec (the Q&A currently
                                                            in Module 1. At the Annex 2 level, it is stated that response documents should be attached to the     2/b/ctd_05-2006.pdf) now defines a specific section in Module 1 for                                                                                          references v1.2.1).
                                                            Cover Letter (1.0). However, no recommendation is given with regard to the organisation of the        Responses to Questions, what to include in Module 1 and what to
                                                            table of contents, nor to the names and organisation of the files etc. Do these recommendations       include in Modules 2-5. The EU Module 1 specification Version                                                                                                LD: Need for guidance when upgrading from
                                                            exist?                                                                                                1.2.1 now includes the section for Responses to Questions. The                                                                                               v1.0 to v1.3 or v1.4 as response to questions
                                                                                                                                                                  CTD guidance and eCTD specification together should give                                                                                                     will have to move from element m1-additional
                                                                                                                                                                  adequate direction for applicants to construct a Responses to                                                                                                to element m1-response (added in v1.2)
                                                                                                                                                                  Questions dossier in eCTD format. The filenaming
                                                                                                                                                                  recommendation is also included in the EU specification v1.2.1.

A009                                                        M3 requires each substance-manufacturer and drug product to be added in a separate subfolder. Change request added retrospectively to allow tracking of the Q&A                 Answered in             closed                                N/A                  No further action required by EU with regard to
                                                            How should a product be added to the structure if it has multiple substances?                 process                                                                           Implemented in EU M1                                                               EU M1 v1.4
                                                                                                                                                                                                                                            v1.4
A012   The question was    eCTD EU Module 1 Specification   Can further clarification be provided on the related sequence element?                                May 2005 - referred to EU and MHLW for regional guidance                  Approval date: 1.2.2008 closed                                N/A                  No further action required by EU with regard to
       generated by change                                                                                                                                                                                                                                                                                                     EU M1 v1.4
       request 00890 /                                                                                                                                            June 2005: To be covered by the EFPIA White Paper on eCTD
       generated by EU                                                                                                                                            LCM.
       Change Requests
       A012 and QA-                                                                                                                                               Feb 2008 : Answered as Question #12
       20070628-01                                                                                                                                                Answer: A 'regulatory activity' is a logical unit of submission
                                                                                                                                                                  activity (eg, a Type II Variation) with a defined start and end point
                                                                                                                                                                  (eg initial submission to final approval). In the eCTD world, this will
                                                                                                                                                                  consist of all the sequences that together make up the lifecycle of
                                                                                                                                                                  that particular 'regulatory activity‟.

                                                                                                                                                                  The related sequence attribute should always be left blank for new
                                                                                                                                                                  applications or new regulatory activities (eg variations, PSURs).
                                                                                                                                                                  When submitting lifecycle sequences within an existing activity,
                                                                                                                                                                  the related sequence attribute should be populated with the
                                                                                                                                                                  sequence number of the first sequence in the activity, regardless of
                                                                                                                                                                  how many sequences make up the activity. The related sequence
                                                                                                                                                                  attribute should be considered independent of any modified file
                                                                                                                                                                  attributes in a submission. For example, if a sequence 0010
                                                                                                                                                                  modifies files (leaves) in sequence 0008 and 0009, the entry for
                                                                                                                                                                  related sequence in sequence 0010 should be the sequence
A013                       eCTD EU Module 1 Specification   From the eCTD experience of the IWG, what parts of the Specification are commonly                     Based on experience, there have been different interpretations of         Approval date: 1.1.2008 closed and covered by EU Validation   N/A                  No further action required by EU with regard to
                                                            misinterpreted that would prevent my eCTD message from being viewed by another                        the eCTD Specification that have prevented timely exchange of                                     criteria.                                                  EU M1 v1.4
                                                            applicant/regulator?                                                                                  eCTD submissions. Those creating and viewing eCTD messages
                                                                                                                                                                  should adhere to the eCTD Specifications (ICH and regional) and
                                                                                                                                                                  consult with regional authorities to avoid these problems. The
                                                                                                                                                                  items in the following list already exist in the Specification 3.2, but
                                                                                                                                                                  have been summarized here to alleviate these problems.
                                                                                                                                                                  Adherence to these items is technically necessary to exchange
                                                                                                                                                                  eCTD messages. Extra controls might hinder the exchange of
                                                                                                                                                                  eCTD messages. The IWG will continue to monitor eCTD
                                                                                                                                                                  implementation to provide additional clarity.
                                                                                                                                                                  May 2005 - referred to EU and MHLW for regional guidance

                                                                                                                                                                  June 2005: Need EU validation criteria.
                                                                                                                                                                  Answer: A list of validation criteria specific to the EU has been
                                                                                                                                                                  prepared by the EURS Implementation Group and is to be
                                                                                                                                                                  published separately on the esubmission website
                                                                                                                                                                  http://www.esubmission.europa.eu
                                                                                                                                                                                                                                                       EU eCTD Specification Change Requests
      #              Requestor                      Specification                                                        Description                                                                             Comments                                    Status                    Action                                    Group Where Action         Notes
                                                     Component                                                                                                                                                                                                                                                                   is Sitting
    0003         EFPIA (A. P. Marr) /                                         How should an applicant handle a Type I variation within and eCTD? Guidance provided in the             Referred as Q&A to Notice to Applicants Group                          Approval date: 1.3.2007 Answered also in CTD Q&A /closed            N/A                        No further action required by EU with regard to
                 generated by EU                                              Notice to Applicants for Type II variations states that they should be organised according to CTD       Answer: The Notice to Applicants group has issued a CTD Q&A                                                                                                           EU M1 v1.4
                 Change Request                                               but for Type IA/IB variations it simply states that they should be organised according to CTD,          regarding the placement of documents within the CTD structure for
                 0003                                                         where applicable. This suggests that there will be occasions when it is not applicable to utilise a     Type I variations. The eCTD should also be constructed using
                                                                              CTD structure and under those circumstances it will not be possible to use the eCTD.                    these principles. The Q&A (4c) can be accessed at
                                                                              Clarification should be provided on how to minimise incompatibilities with the eCTD since it is         http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-
                                                                              impossible to construct an eCTD that is not CTD compliant                                               2/b/ctd_qa_05_2006.pdf




    0004         Fujisawa GmbH (M.      EU Module 1 envelope                  Notice to applicants “Volume 2A/ Procedures for marketing authorisationChapter 1/ Marketing             More understanding of eCTD LCM required for resolution                 Approval date: 1.3.2007 closed. Refers to list of submission types N/A                         No further action required by EU with regard to
                 Hamzakadi) /                                                 Authorisation/February 2004” describes 4 types of Marketing authorisation procedures (p.3-6) as                                                                                                        (already responded to in CR-20070926-01).                              EU M1 v1.4
                 generated by EU                                              follows: - Centralised procedure - Mutual recognition procedure- Independent National                   Referred to Notice to Applicants Group
                 Change Request                                               procedures- Community referrals. In comparison with this, the appendix 1: Envelope Element              Answer: The EU Module 1 specification defines the submission
                 0004                                                         Description” of the EU Module 1 Specification v1.0 document do not include the “Community               types that are part of the eCTD (V1.2.1, p10). The submission type
                                                                              referrals” for the element “procedure” as valid value. The list of valid values for the “type” of       to be used in this instance is 'arbitration'. [Note, since this
                                                                              procedure for the submission should be adapted i.e. a new value “community referrals” should be         question was originally received, the EU has added the
                                                                              added if possible?                                                                                      Decentralised Procedure as an acceptable submission procedure
                                                                                                                                                                                      type.]



QA-20061120-01   Alastair Nixon, GSK                                          When submitting via the centralised procedure, changes are frequently required to the dossier           Nov-07 Part i) Accepted for Q&A                                        Approval date: 1.2.2008 closed                                      N/A                        No further action required by EU with regard to
                                                                              following validation by the EMEA. At present, the rapporteur and co-rapporteur have at this stage       Part ii) was referred to eCTD Interlinking group, they responded "It                                                                                                  EU M1 v1.4
                                                                              already received an initial copy of the eCTD.                                                           is required to submit the application to Rap / Co-Rap at the same
                                                                              (i) How is the applicant advised to handle validation changes in the eCTD? Should another               time as to the EMEA. It is therefore not possible to submit to Rap /
                                                                              eCTD sequence be created, incorporating the suggested changes, or should the original                   Co-Rap only after validation of the application."
                                                                              sequence be corrected? NB If an additional sequence were to be provided, the assessor would             Answer: If an eCTD fails technical validation, then a replacement
                                                                              need to view both sequences in „current‟ view in an eCTD viewer. Further, if the original               sequence must be provided, since an invalid sequence cannot be
                                                                              submission was not 0000, in some eCTD viewing tools, it is currently not possible to view the           loaded into an agency‟s review tool. If, once technical validation
                                                                              „current‟ content of selected sequences only – the tool will only allow the user to view the current    has been completed, content validation identifies missing sections
                                                                              view of all submitted sequences.                                                                        or administrative errors, then an additional new eCTD sequence
                                                                              (ii) What is the EMEA‟s view on provision of copies of the electronic dossier for the rapporteur        should be provided (a lifecycle sequence) correcting these errors,
                                                                              and co-rapporteur? Could this be delayed until after validation, to prevent industry having to          with replacement or additional new documents as required. The
                                                                              submit either updated original sequence or 2 sequences?                                                 applicant should not send a replacement of the original sequence.




QA-20070628-01   Thierry Le Ridant,     eCTD EU Module 1 specification v1.2.1 During a sequence 0026, we must modified SPC of the 0020 sequence and leaflet of the 0022               Nov-07 Both proposals are considered incorrect. A Q&A has been see A012                          closed                                    N/A                        No further action required by EU with regard to
                 Ethypharm                                                    sequence.                                                                                               drafted to clarify use of related-sequence attribute                                                                                                                  EU M1 v1.4
                                                                              What should be the value of the <related-sequence> in the <envelope>? The last sequence                 See also CR A012
                                                                              modified (0022) or it should be blank?                                                                  See Question 12


CR-20070928-01   Leo van de Winkel,     Notice to Applicants vol 2B           The ASMF guidelines state that the manufacturer and the applicant should both submit an                 Nov-07 This issue is referred to the NtA Q&A on handling of ASMF Accepted - refer to             Subgroup of Interlinking group to be       eCTD Interlinking Group
                 N.V. Organon                                                 identical Applicant‟s Part (AP) of the EDMF.                                                            March-09 : Subgroup of Interlinking group to be established to   eCTD Interlinking Group         established to produce guidance for ASMF -
                                                                              Guidelines for eCTD files indicate that the AP should be included in Section 3.2.S of the eCTD.         produce guidance for ASMF                                        7/2010 - move to closed          draft practical/technical guidance to be
                                                                              Section 3.2.S does not allow the AP to be included as one document; the AP should be                    7/2010 - in ASMF guide published                                                                 published by end 2009 (following a meeting
                                                                              separated in parts reflecting the CTD structure and the general parts of the AP can not be                                                                                                               scheduled 14th December).
                                                                              included in 3.2.S.
 CR-20080703     Andrew Marr (EFPIA) EU M1 Specification v1.3                 The list of submission types included in the eCTD Module than it is not identical anymore to the
                                                                              Conclusion: if the AP of the EDMF is included in part 3.2.S1 specification v1.3 does not include        As part of the creation of EU Module 1, v1.3 and in conjunction with   Accepted - refer to Q&A   Produce Q&A and update Best Practice      eCTD Interlinking Group
                                                                              Repeat Use Procedure. What submission type should be used for this submission?                          the development of the eCTD in MRP/DCP Best Practice document          and include in updated    Guidance
                                                                                                                                                                                      consideration was given to the creation of „Repeat Use Procedure‟      Best Practice Guidance
                                                                                                                                                                                      as a specific submission type. After deliberation, this was not        7/2010 - move to closed
                                                                                                                                                                                      accepted. However, the Best Practice Guide did not include any
                                                                                                                                                                                      recommendation for which submission type should be used. In
                                                                                                                                                                                      discussion at the eCTD Interlinking Group it was proposed that
                                                                                                                                                                                      „Initial MAA‟ should be used and that a Q&A should be prepared to
                                                                                                                                                                                      this effect.
                                                                                                                                                                                      The submission type that should be used is „initial-maa‟ since this
                                                                                                                                                                                      is the initiation for the new Concerned Member States. The
                                                                                                                                                                                      submission description should be „Repeat Use Procedure‟.
                                                                                                                                                                                      March-09 : Interlinking agreed that as an interim, a Q&A would be
                                                                                                                                                                                      produced and in the longer-term update the Best Practice guide.
                                                                                                                                                                                      7/2010 - Included in Best Practices Guide

CR-20080703-01   Andrew Marr (EFPIA) EU M1 Specification v1.3                 The list of submission types included in the eCTD Module 1specification v1.3 does not include a As part the development of the eCTD in MRP/DCP Best Practice                   Accepted - refer to       Produce Q&A                               eCTD Interlinking Group
                                                                              specific submission type for a change of the Reference Member State in MRP. What submission document it was agreed that „Change of RMS‟ would utilise an                       eCTD Interlinking
                                                                              type should be used for this submission?                                                        existing submission type and that a Q&A should be prepared to this             Group;
                                                                                                                                                                              effect.                                                                        7/2010 - move to closed
                                                                                                                                                                              The submission type that should be used is „supplemental-
                                                                                                                                                                              information‟ and the submission description should be „Change of
                                                                                                                                                                              Reference Member State‟
                                                                                                                                                                              March-09 : CMD(h) reviewing guidance on change of RMS. Q&A to
                                                                                                                                                                              be produced to explain how change should relate to eCTD.
                                                                                                                                                                              7/2010 - In Best Practices Guide

 CR-20090126                            NtA Volume 2B Section 2.7.6           The ICH M2 eCTD specification and Notice to Applicants Volume 2B provide different information          TIGes 6 March 09 : Principle supported. Action to Interlinking       Answered in                 closed                                    N/A                        Include notes from the Q&A #22 in the EU M1
                                                                              concerning how to deal with the Synopses of Individual Studies in Section 2.7.6. The guidance           Group to progress. Suggested that option of either hyperlinking to Implemented in EU M1                                                                               v1.4.
                                                                              should be harmonised to provide a similar message in both the CTD and eCTD and avoid                    or inclusion of synopses.                                            v1.4
                                                                              confusion.                                                                                              Recommend that the NtA guidance is updated to reflect the
                                                                              The NtA guidance states:                                                                                Section 2.7.6 guidance in the ICH M2 eCTD or clearly reference
                                                                              2.7.6 Synopses of Individual Studies                                                                    this difference between the paper and electronic outputs.
                                                                              The ICH E3 guideline (Structure and Content of Clinical Study Reports) suggests inclusion of a          March-09 : Interlinking agreed that hyperlinking should be an option
                                                                              study synopsis with each clinical study report, and provides one example of a format for such           for applicants. Q&A to be produced.
                                                                              synopses.                                                                                               April-09 : Interlinking group endorsed a Q&A for publication
                                                                              This section should include the table entitled Listing of Clinical Studies, described in guidance for
                                                                              Module 5, followed by all individual study synopses organised in the same sequence as the study
                                                                              reports in Module 5.
                                                                              It is expected that one synopsis will be prepared per study for use in all regions, and that the
                                                                              same synopsis will be included in this section and as part of the clinical study report in Module 5.
                                                                              The length of a synopsis will usually be up to 3 pages, but a synopsis for a more complex and
                                                                              important study may be longer, e.g. 10 pages. Within the individual synopsis, tables and figures
                                                                              should be used as
                                                                              appropriate to aid clarity.
                                                                              But the ICH M2 eCTD guidance states:
                                                                              These synopses should already be located in the Clinical Study Reports in Module 5 and should
                                                                              not, therefore, be repeated in
                                                                              Module 2. It is considered sufficient to provide hyperlinks from the listing
                                                                              of the studies, located here, to the locations of the synopses in Module 5.
                                                                                                                                                                                                                                                    EU eCTD Specification Change Requests
    #             Requestor                     Specification                                                          Description                                                                            Comments                                    Status                        Action                                         Group Where Action        Notes
                                                 Component                                                                                                                                                                                                                                                                             is Sitting
CR-20090527   Donald Palmer,       EU eCTD Validation Criteria v 2.1       In looking through the EU eCTD Validation Criteria, it would appear that #29 and #45 are in            Discussed in CR subgroup 20091210. Proposal agreed, but                 Accepted;                     Amend EU eCTD validation criteria with    Harmonisation Group
              MedImmune                                                    conflict, if MS Word documents are included with the PDF formats in the same folder.                   implement with slightly different wording (take wording from EMEA       7/2010 - Follow-up with       new wording. Publish as v2.2. Discuss in
                                                                           Criteria #29 explicitly states that the MS Word files should not be in the eCTD backbone and be        practical/technical guidance).                                          EURS group [G.                relation to the update of the Validation
                                                                           in the same folder (as the PDF). This would conflict with #45, which states that there are no                                                                                  Isakkson]                     Criteria.
                                                                           unreferenced files in M1-M5 folders.                                                                                                                                           9/2010 - Redirected to        Harmonisation Group: The issue was
                                                                                                                                                                                                                                                          Harmonisation Group           addressed and clarified when updating the
                                                                           Change validation criterion #29 to clarify that "MS Word files, if requested, should not be included                                                                           2/2011 - Completed            validation criteria for eCTD version 3.0
                                                                           in the eCTD backbone but provided                                                                                                                                                                            published in January 2011 and coming into
                                                                           separately" (i.e. remove reference to "in the same directory").                                                                                                                                              force by 1 September 2011.
CR-20090615   Alastair Nixon GSK   Currently no guidance, reference made   Replacing documents across sections (eCTD elements - should be allowed or not? This is                 Discussed at TIGes, Sep-09.                                             Accepted - refer to Q&A       11/16/2010 for Q&A                        10/2010 - Write Q&A #23 -      Include notes from the Q&A #23 in the next EU
                                   in EURS meeting notes, October 2008.    particularly relevant in the EU, where, for submissions containing content not yet in the DTD,         Accepted as not good practice to carry out lifecycle across             7/2010 - Follow-up with       Also when M1 is updated                   G. Williams                    M1 revision.
                                                                           applicants are encouraged to use m1-additional-data, then revert to the new section once               sections, though there are specific occurrences when this might         Interlinking Group                                                      1/2011 - Move to Closed as
                                                                           available. Should the new document in the new location „replace‟ the original in m1-additional-        happen (transition guidance and changes to section names).              9/2010 - Interlinking                                                   Q&A #23 finalised
                                                                           data, or should the document have the operation attribute of „new‟, and the version in m1-             Q&A to be created                                                       updated - G. Williams
                                                                           additional deleted? In general, can some guidance be provided on the validity of using replace or      Include statement in next version of specification/guidance             actioned
                                                                           delete operation attribute on a document which is no longer in the same location as the                7/2010 - only needed when next minor version required because of        10/2010 - Interlinking
                                                                           document that is being replaced or deleted?                                                            M1 section additions, not urgent                                        Group - Proposal
                                                                                                                                                                                  9/2010 - Agree that it should be a delete in the current section and    agreed. Q&A to be
                                                                                                                                                                                  a replace in the new.                                                   drafted for Interlinking in
                                                                                                                                                                                  10/2010 - Interlinking agreed on following :                            November
                                                                                                                                                                                  CR is accepted.                                                         1/2011 - Q&A finalised;
                                                                                                                                                                                  Agreement that the solution should be to 1) delete the original         CR Closed
                                                                                                                                                                                  document in the m1-additional data and 2) add a new document in
                                                                                                                                                                                  the correct place holder.
                                                                                                                                                                                  Geoff Williams to write a Q&A. The Q&A will be ready for
                                                                                                                                                                                  discussion/agreement in November.
                                                                                                                                                                                  Q&A will consist of two sections.
                                                                                                                                                                                  1) The answer will explain that the cross-linking is only allowed for
                                                                                                                                                                                  specific transition periods, in which additional data is used and
                                                                                                                                                                                  later the DTD defines the correct place
                                                                                                                                                                                  2) That this practise should not be used normally across sections
                                                                                                                                                                                  in eCTD
                                                                                                                                                                                  1/2011 - Since all Q&As will be incorporated into the revised M1
                                                                                                                                                                                  guidance, this CR will be closed.


CR-20090630   Karin Grondahl,      EU eCTD Validation Criteria v 2.1       Due to national archive requirements for ISO standard for PDF/A that is based on PDF 1.4, it is        Discussed at TIGes, Sep-09.                                             Accepted - refer to           9/2010 - Refer to Harmonisation Group for Harmonisation Group
              MPA, Sweden                                                  needed as an “A” criterion.                                                                            No decision as parties could not agree                                  Interlinking Group            consideration with validation criteria update
                                                                           Recommended solution to change categorisation from 'B' to 'A'.                                                                                                                 7/2010 - Follow-up with       Harmonisation Group: The issue was
                                                                                                                                                                                  Discussed in CR Subgroup 20091210. More feedback on this                Interlinking Group            addressed and clarified when updating the
                                                                                                                                                                                  needed from MPA. As this CR relates to SE national archive              9/2010 - Transitioned to      validation criteria for eCTD version 3.0 and
                                                                                                                                                                                  requirements, then national arrangements should be made but the         Harmonisation Group           NeeS version 2.0 published January 2011
                                                                                                                                                                                  specification should not change. Proposal to reject the CR,             2/2011 - Completed            and coming into force by 1 September
                                                                                                                                                                                  pending further feedback.                                                                             2011. PDF 1.4 should normally be used
                                                                                                                                                                                  7/2010 - could be progressed as part of consideration for use of                                      and earlier versions are not accepte
                                                                                                                                                                                  ISO 32000 (PDF 1.7) being discussed at ICH                                                            (Pass/Fail criteria). The need for including
                                                                                                                                                                                  10/2010 - Interlinking agreed on following:                                                           PDFs of later versions should be
                                                                                                                                                                                  Issue should be referred to the Harmonisation group, which is                                         explained, but is not a Pass/Fail criteria.
                                                                                                                                                                                  responsible for the review of the validation criteria.


CR-20090701   Remco Munnik,        EU eCTD Validation Criteria v 2.0       For the NeeS validation criteria it was added that for file security modules 4.3 and 5.4 should be     Discussed at TIGes, Sep-09.                                             Accepted - refer to           9/2010 - Discussed in relation to the          Harmonisation Group
              Sandoz                                                       excluded from a check:                                                                                 Referred to Harmionisation Task Force to identify suitable wording      Harmonisation Group           update of the Validation Criteria.
                                                                           “Security Settings:                                                                                    for the next version of the guidance document.                          7/2010 Follow-up with         Harmonisation Group: The issue was
                                                                           There is no security setting on any file in the submission, (does not apply to files located in 4.3    7/2010 Should be progressed together with CR 20090903.                  Harmonisation Group           addressed and clarified when updating the
                                                                           and 5.4)”                                                                                                                                                                      9/2010 - Harmonisation        validation criteria for eCTD version 3.0 and
                                                                                                                                                                                                                                                          Group updated                 NeeS version 2.0 published January 2011
                                                                           In order to align the eCTD validation criteria with the NeeS validation criteria, this CR is                                                                                   2/2011 - Completed            and coming into force by 1 September
                                                                           submitted to add the exception for the eCTD validation criteria, nr 41:                                                                                                                                      2011.
                                                                           “There is no security setting or password protection on any individual file”.

CR-20090820   Bernadette Billet    EU M1 v1.4                              The <related-sequence> element is declared in the EU v1.4 envelope.mod file with an optional           Discussed at TIGes, Sep-09.                                             Answered in Q&A               Answered as Q&A #24                            N/A
                                                                           country attribute. This attribute was removed in the v1.3 revision of the specification and is not     This was acknowledged as an error, there should be no country
                                                                           mentioned in the text of the v1.4 specification. Should this attribute ever be used?                   identifier on the related sequence.
                                                                                                                                                                                  An immediate Q&A should be drafted to prevent software vendors
                                                                                                                                                                                  from building this into tools for v1.4
                                                                                                                                                                                  Correct in next version of specification.
CR-20090903   Alastair Nixon GSK   EU eCTD Validation Criteria v 2.1       In the EU validation rules, there are 6 modified file checks. The first (rule 15) checks that no       Discussed by CR subgroup 20091210. Proposal accepted for                Accepted                      Update EU eCTD validation criteria v2.1        Harmonisation Group
                                                                           modified file references an invalid document, but has the proviso that submissions may be              implementation in the validation criteria. The revised EU M1            7/2010 CCB                    based on proposal from AN.
                                                                           received out of order, and the sequence containing the leaf with the ID in the modified file           validation criteria v2.2 should be issued with a note indicating that   recommends moving to          Harmonisation Group: The issue was
                                                                           attribute might not yet be loaded into the system. Therefore, if the system cannot find the ID in      implementation/compliance from tool vendors is expected within 6        Harmonization Taskforce       addressed and clarified when updating the
                                                                           previous lifecycle, only a warning should be given (Cat C).                                            months of publication. Publication of v2.2 should also include          9/2010 - Harmonisation        validation criteria for eCTD version 3.0 and
                                                                                                                                                                                  guidance to regulators, indicating that if errors/warnings on the       Group updated                 NeeS version 2.0 published January 2011
                                                                                                                                                                                  modified file are received during the transition period, then they      2/2011 - Completed            and coming into force by 1 September
                                                                                                                                                                                  should contact the applicant before rejecting the submission on                                       2011.
                                                                                                                                                                                  those grounds.
                                                                                                                                                                                  7/2010 Highest priority, content of CR superseded by more recent
                                                                                                                                                                                  version submitted June 14th (same number); eCTD TG
                                                                                                                                                                                  recommended bringing together all the validation CRs.
CR-20091016   Karin Grondahl,      Best Practice Guideline “Guidance for  If an applicant has an old dossier in mixed format, Module 1-3 in CTD format and Module 4-5 in          If the dossier is not totally changed into CTD format, the eCTD         Accepted - refer to           Produce first draft of guidance to go in the   eCTD Interlinking Group
              MPA, Sweden          Industry on Providing Regulatory       the old NtA format (Part 4-5), how should it be submitted when changing over to eCTD format?            could only contain Modules 1-3 and the old parts have to be kept in     eCTD Interlinking Group       BPG
                                   Information in Electronic Format: eCTD                                                                                                         NtA format outside the eCTD , but in what format?                       7/2010 - move to closed
                                   electronic Submissions                                                                                                                                                                                                                               Assigned to KG (MPA)
                                                                                                                                                                                  Discussed at TIGes/NtA Interlinking Meeting 20/10:
                                                                                                                                                                                  The CTD guidance allows applicants to send modules 4&5 in old
                                                                                                                                                                                  NtA format (in repeat use MRP only). For submission in electronic
                                                                                                                                                                                  format, 2 options were proposed: submission of modules 4&5 in
                                                                                                                                                                                  paper with the remainder electronic, or convert into CTD and
                                                                                                                                                                                  submit all modules electronically.
                                                                                                                                                                                  If full electronic format is produced, this should follow the CTD
                                                                                                                                                                                  structure as normally required. Additional guidance/clarification of
                                                                                                                                                                                  these options are needed in the eCTD Best Practice Guide for
                                                                                                                                                                                  MRP/DCP.
                                                                                                                                                                                  7/2010 - Included in Rev 1 of Best Practices Guide as section 4.10
                                                                                                                                                                                                                                                      EU eCTD Specification Change Requests
      #               Requestor                    Specification                                                          Description                                                                            Comments                                   Status                    Action                                          Group Where Action             Notes
                                                    Component                                                                                                                                                                                                                                                                         is Sitting
 CR-20091116     Caroline Keller,       EU eCTD Validation Criteria v 2.1      The NeeS validation criteria 0005 for EU M1 filenaming convention is stricter for 1 of the items    Harmonisation Taskforce are responsible for NeeS Guidance and            Accepted - refer to       Discuss in relation to the update of the        Harmonisation Group
                 Novartis Pharma                                               listed: “the variable part, if used, does not include hyphens”. This criteria is listed as an A     validation criteria.                                                     Harmonisation Group       Validation Criteria.
                                                                               Category.                                                                                                                                                                    7/2010 Follow up with     Harmonisation Group: The issue was
                                                                               In the eCTD validation criteria, the number 35 for following EU filenaming convention is classified                                                                          Harmonisation Group       addressed and clarified when updating the
                                                                               as a B.                                                                                                                                                                      9/2010 - Harmonisation    validation criteria for eCTD version 3.0 and
                                                                               This difference makes it somewhat confusing for the applicant and also more difficult to                                                                                     Group update              NeeS version 2.0 published in January
                                                                               implement if too rigid.                                                                                                                                                      2/2011 - Completed        2011 and coming into force by 1
                                                                                                                                                                                                                                                                                      September 2011.
                                                                               Since the use of hyphens is no showstopper for the use of the NeeS submission, the proposal is                                                                                                         The naming convension is a Pass/Fail
                                                                               to have the NeeS criteria 0005 changed to match the eCTD criteria 33 and 35, including the                                                                                                             criteria for NeeS module 1-3 as this is the
                                                                               prioritization.                                                                                                                                                                                        main navigation aid. For eCTD it is only a
                                                                                                                                                                                                                                                                                      BP test since the XML is the main
                                                                                                                                                                                                                                                                                      navigation tool. Hyphens is accepted.

CR-20091116-01   Caroline Keller,       EU eCTD Validation Criteria v 2.1      The NeeS validation criteria 0011 for the pdf version is listed as an A issue, while this is only a B   Harmonisation Group are responsible for NeeS Guidance and            Accepted - refer to       Discuss in relation to the update of the      Harmonisation Group
                 Novartis Pharma                                               issue in the eCTD validation criteria (#37). Moreover, the comment of the NeeS criteria indicates       validation criteria.                                                 Harmonisation Group       Validation Criteria.
                                                                               that there are some national exceptions, which makes it somewhat confusing.                                                                                                  7/2010 Follow up with     Harmonisation Group: The issue was
                                                                                                                                                                                                                                                            Harmonisation Group       addressed and clarified when updating the
                                                                               Recommendation: Turn the NeeS validation criteria 0011 to a B category.                                                                                                      9/2010 - Harmonisation    validation criteria for version 3.0 published
                                                                                                                                                                                                                                                            Group update              in January 2011 and coming into force by 1
                                                                                                                                                                                                                                                            2/2011 - Completed        September 2011. (see CR-20090630)
CR-20091116-02   Caroline Keller,       EU eCTD Validation Criteria v 2.1      The NeeS validation criteria 0012 for the pdf quality (no broken hyperlinks and bookmarks) is           Harmonisation Taskforce are responsible for NeeS Guidance and        Accepted - refer to       Discuss in relation to the update of the        Harmonisation Group
                 Novartis Pharma                                               listed as an A issue, while this is only a B issue in the eCTD validation criteria (#38 and 41).        validation criteria.                                                 Harmonisation Group       Validation Criteria.
                                                                                                                                                                                                                                                            7/2010 Follow up with     Harmonisation Group: The issue was
                                                                               Recommendation: Turn the NeeS validation criteria 0012 to a B category.                                                                                                      Harmonisation Group       addressed and clarified when updating the
                                                                                                                                                                                                                                                            9/2010 - Harmonisation    validation criteria for eCTD version 3.0 and
                                                                                                                                                                                                                                                            Group update              NeeS version 2.0 published in January
                                                                                                                                                                                                                                                            2/2011 - Completed        2011 and coming into force by 1
CR-20091217-01   Alastair Nixon GSK     EU eCTD Validation Criteria            The current eCTD validation criteria (v2.1) contain tests specific to version 1.3 of the European       Discussed by trial CCB 20100517;                                     Accepted - referred to    September 2011.
                                                                                                                                                                                                                                                                                      Discuss in relation to the update of the        Harmonisation Group
                                                                               Module 1 specification. Specifically, test 35 requires that, “EU M1.3 file name convention is           We recommend refining the text so the revised text does not go out   Harmonisation Group for   Validation Criteria.
                                                                               followed”. This test should refer to the current EU m1 specification, or, ideally, refer to all         of date as well [cited link]                                         implementation            Harmonisation Group: The issue was
                                                                               currently allowable versions of EU Module 1. Test 2 states that “A valid EU M1 DTD exists”, but         10/2010 - Interlinking agreed on following:                          9/2010 - Update by        addressed and clarified when updating the
                                                                               this does not disallow earlier DTDs which should no longer be used.                                     Issue should be referred to the Harmonisation group, which is        Harmonisation Group       validation criteria for eCTD version 3.0
                                                                                                                                                                                       responsible for the review of the validation criteria.               10/2010 - Interlinking    published in January 2011 and coming into
                                                                                                                                                                                       Follow-up: Already being addressed by Harmonisation Group in         agreed to refer back to   force by 1 September 2011.
                                                                                                                                                                                       validation criteria work                                             Harmonisation Group.
                                                                                                                                                                                                                                                            2/2011 - Completed
 CR-20100107     Andrew Marr, GSK       eCTD MRP/DCP Tracking Table            The eCTD in MRP/DCP best practice guide has been revised and now includes a description for             Discussed by trial CCB 20100517; follow-up with author indicated     Accepted                  move to Closed CRs page after TIGes 3           Interlinking adoption paper,
                                        specification                          the change to the RMS. The current specification for the xml table does not support a change of         that the Interlinking group has already Accepted and a paper for                               June 2010                                       trial CCB for tracking
                                                                               RMS. Only one is allowed. The specification should be amended.                                          adoption is being drafted
 CR-20100517     Cynthia Piccirillo,    Change Control Process for European    Stakeholders reported that TIGes meetings frequently have its performance badly affected by             Discussed by trial CCB 20100517                                      Accepted                  Move to Duplicated CRs after TIGes 3            Joint TIGes
                 BMS                    eCTD Standards V1.1                    long discussions taking place regarding change requests. Also, given TIGes meetings occur                                                                                                              June 2010
                                        Document J03-CR Processing Steps-      quarterly, decisions might take up to 3 months or longer to be closed. An improved Change
                                        20070907, version date 2007-09-07      Request process would achieve many benefits.
 CR-20100930     Remco Munnik,           EU NeeS guidance                      Applicants receive comments from Health Authorities about missing ToC‟s (m1.1, 2.1, 3.1, 4.1            Clarify in the NeeS guidance document that there is no need for a    CCB 9/2010 - Accepted,    Harmonisation Group: The issue was              Harmonisation Group
                 Sandoz                                                        and 5.1) for NeeS applications.                                                                         paper ToC in sections 1.1, 2.1, 3.1, 4.1 and 5.1                     referred to               addressed and clarified when updating the
                                                                               According to the ICH granularity document, there is no need for ToC for eCTD submissions. The           CCB 10/2010 - We agree with the proposal and add that the PDF        Harmonisation Group       validation criteria for NeeS version 2.0
                                                                               XML files function as a ToC and therefore modules 1.1, 2.1, 3.1, 4.1 and 5.1 are not applicable. It     ToC actually provides better navigation capability due to the                                  published January 2011 and coming into
                                                                               states therein, “The TOC is only called for in the paper version of the CTD; there is no entry          hyperlinks. The guidance to amend is not the NeeS guidance but                                 force by 1 September 2011. The TOCs is
                                                                               needed for the eCTD.”                                                                                   the "Practical Guidance For the Paper Submission of Regulatory                                 not needed in 1.1, 2.1, 3.1, 4.1, 5.1 for the
                                                                               For a NeeS application, PDF ToC‟s are provided that replace the xml files and that link to all          Information in Support of a Marketing Authorisation Application                                electronic submissions as the hyperlinked
                                                                               available files in the dossier.                                                                         When Using an eCTD or a NeeS as the Source Submission" v2.0,                                   TOCs serve the purpose for navigation.
                                                                               From an applicant‟s perspective, we assumed that there is no need for modules 1.1, 2.1, 3.1, 4.1        March 2010. Suggested is only to print ToCs for modules that are
                                                                               and 5.1 for a NeeS application.                                                                         actually printed.
 CR-20101025     Danilo Šteblaj,        Guidance for Industry on Providing     Chapter 2.2 says that NeeS submissions have the same folder structure as eCTD, which is not             Solution proposal to the above mentioned problems is attached in     11/2010 - Accepted,       While the change request has been             Harmonisation Group
                 Agency for Medicinal   Regulatory Information in Electronic   correct (no sequence folder in NeeS, the top level folder is the same with each submission in           file JAZMP_CR_NeeS.docx.                                             referred to               accepted, the CCB recommends revision
                 Products and           Format:                                eCTD, in NeeS it changes, index.xml, eu-regional.xml files and util folder are not present in NeeS                                                                           Harmonisation Group       to the proposed solution as follows: It is
                 Medical Devices of     Non-eCTD electronic Submissions        submissions). There is no system described for creating the name of the top level folder (in            Need to send to Harmonisation Group                                  2/2011 - Completed        true, that no index.xml and util folder are
                 the Republic of        (NeeS) for human medicinal products    practice this leads to constant changing of the top level folder and subsequently to inability to                                                                                                      present. But the re-worded validation
                 Slovenia                                                      identify the documentation/correlation between different submissions or supplement                                                                                                                     criteria will clarify a number of part
                                                                               documentation).                                                                                                                                                                                        addressed, e.g. “4 digit number folder”, top
                                                                                                                                                                                                                                                                                      level folder and naming convention for it,
                                                                               Also in NeeS there is no tracking table (no life cycle), so it is much harder to figure out, which                                                                                                     the placement of ctd-toc.pdf and module
                                                                               submissions are the parts of the same regulatory activity. There should be an appropriate                                                                                                              TOC files. The request can be partly
                                                                               substitute for tracking table (information at the end of the cover letter).                                                                                                                            accepted, but should be perhaps re-
                                                                                                                                                                                                                                                                                      worded according to the new validation
                                                                               Because it happened several times in practice, that the ToC was present in module 1.1, the                                                                                                             criteria before the CR is forwarded to the
                                                                               following sentence should be added in the chapter 2.2.1:                                                                                                                                               harmonisation group.
                                                                                                                                                                                                                                                                                      By the way, folder similar to eCTD
                                                                               The module 1.1 should not be present in NeeS submission, as it is replaced by general ToC                                                                                                              sequence folder can be provided as well
                                                                               (located in top level folder for the submission) and module specific ToCs (located in the                                                                                                              and doing so, a tracking table is valuable to
                                                                               corresponding top level module folder).                                                                                                                                                                keep track of received submissions. In the
                                                                                                                                                                                                                                                                                      past we have tried a keep NeeS as close
                                                                               The text from the chapter 2.3 should be included in chapter 2.2, the chapter 2.3 should therefore                                                                                                      as possible to eCTD. This approach will
                                                                               be deleted.                                                                                                                                                                                            clearly skipped if the CR will be accepted
                                                                                                                                                                                                                                                                                      without changes. But it was also common
                                                                               The part of text in chapter 2.5.1 should be deleted, because it contradictory to theory.                                                                                                               sense that NeeS is not the format we want
                                                                                                                                                                                                                                                                                      to promote. Therefore, we should avoid
                                                                               Also the pictures in chapters 2.9.3 and 2.12.5 should be replaced, as they are contradictory to the                                                                                                    anything which differentiates NeeS from
                                                                               text.                                                                                                                                                                                                  eCTD more than necessary. From
                                                                                                                                                                                                                                                                                      practical point of view: several companies
                                                                                                                                                                                                                                                                                      produce eCTD submission and skip the util-
                                                                                                                                                                                                                                                                                      folder etc. and added the TOC files for
                                                                                                                                                                                                                                                 EU eCTD Specification Change Requests
      #              Requestor                   Specification                                                         Description                                                                           Comments                                 Status                 Action                                        Group Where Action    Notes
                                                  Component                                                                                                                                                                                                                                                                is Sitting
CR-20110127-02   Geoff Williams,     EU eCTD Validation Criteria v 2.1 and   Several areas have been updated as a result of the review carried out by the TIGes                    This is a high level Change Request to capture the major changes   2/2011 - Accepted as   The changes identified have been applied      Harmonisation Group   Created retrospective of changes made to
                 Roche, for          EU NeeS Validation Criteria v 1.0       Harmonisation Group. These are:                                                                       made to the eCTD and NeeS validation criteria by the TIGes         Completed              during the TIGes Harmonisation Group                                ensure traceability for those revisions that
                 Harmonisation Group                                         Principles for Validation Criteria                                                                    Harmonisation Group that are not captured in other individual                             review of the validation criteria that took                         were not the result of an existing CR. Thus
                                                                             The following principles have been applied during the review:                                         change requests. The list is not exhaustive and detailed to the                           place between September, 2010 and                                   accepted as 'completed'.
                                                                             1. Each identified criterion must be a check for a single item.                                       finest degree as this would not be possible given the degree of                           January 2011.
                                                                             2. Each criterion must be defined in an unambiguous way that leaves no room for interpretation        change undertaken. However, key changes and principles for the
                                                                             3. The criteria must be defined in a way that is tool and vendor independent                          changes are noted.
                                                                             Changes to Priority
                                                                             The eCTD priority rankings of A, B and C were not felt to be completely understood. In addition,
                                                                             the A ranking of all NeeS criteria was not felt to address some areas that made the NeeS easier
                                                                             to use.
                                                                             Criteria are now rated Pass/Fail or Best Practice. Further explanation can be found in the criteria
                                                                             and in the release notes and business process document.
                                                                             Alignment Between eCTD and NeeS Criteria
                                                                             Wherever possible the wording of criteria have been aligned. Where it makes sense, the type of
                                                                             check has also been aligned, though cases exist where the same check has different
                                                                             categorisation for eCTD than for NeeS.
                                                                             Layout and Presentation
                                                                             A change Control worksheet has been added.
                                                                             The “source” column has been removed as it was unnecessary and often wrong. An additional
                                                                             comments column has been added to clarify understanding and expectations. For the eCTD
                                                                             a column identifies checks that can only be made in the context of other eCTD sequences.
                                                                             File and Folder Naming
                                                                             Additional worksheets to list expectations for file and folder naming, along with specifying the
                                                                             picklists for some parts of Moduel 1 file and folder names, have been added.
                                                                                                                                                                                                        EU eCTD Specification Change Requests
       #          Requestor        Specification                                Description                                            Comments                       Status             Action                                Group Where Action   Notes
                                   Component                                                                                                                                                                                   is Sitting
0012           EMEA (J. Rueda)    eCTD EU Module        The list of submission types accepted in eCTD format listed      EMEA to prepare a list to be confirmed       Duplicated         None                                  N/A                  No further action required by EU
                                  1 Specification       in the eCTD specification should be in line with the list of     at the eCTD interlinking.
                                                        submission types listed as accepted in NtA Volume 2.             Nov 2007 - still under consideration and
                                                        Currently, the 2 lists are not consistent with one another.      now linked to additional CRs - QA-
                                                                                                                         20070906-01 & CR-20070926-01


CR-20061120-   Shy Kumar,         eCTD EU Module        The example submission directory structure for MRP               Mar-07 After discussion, it was agreed Duplicated               None                                  N/A                  No further action required by EU with regard
02             Datafarm           1 specification       (Appendix 3) may be inconsistent with the accompanying           that the examples are correct and do not                                                                                   to EU M1 v1.4
                                  v1.2.1                statement that „common‟ is the directory to hold all files       require changing.
                                                        applicable to more than one country                                                                                                                                                         Covered by CR-20090506


QA-20071022- Alastair Nixon,                            In the eCTD, how should an applicant handle multiple             Nov-07 Best Practice guide written for       Accepted - refer   Ensure this is addressed as part of   N/A                  No
     01      GSK                                        variations that occur in parallel and affect the same            review and approval                          to eCTD            the analysis of the new variation
                                                        document?                                                        March-09 : Subgroup to be established        Interlinking       regulation.
                                                                                                                         to address all issues of variation, in the   Group;             Present guidance for consideration
                                                                                                                         context of the new Variations                7/2010             by Interlinking
                                                                                                                         Regulations. This CR will be addressed       duplicate to row
                                                                                                                         within this group.                           8, will move to
                                                                                                                                                                      duplicated CRs

CR-20091116-   Caroline Keller,   NtA Volume 2B         Could you clarify how the section 2.7.6 should be handled?                                                    Duplicated         None                                  N/A                  Refer to 20090126 and Q&A #22
03             Novartis Pharma    Section 2.7.6         The Notice to Applicant for section 2.7.6 states “This section
                                                        should include the table entitled Listing of Clinical Studies,
                                                        described in guidance for Module 5, followed by all
                                                        individual study synopses organised in the same sequence
                                                        as the study reports in Module 5.” This seems to be not in
                                                        line with the eCTD rules as this leads to duplication of the
                                                        document.

                                                        The eCTD rules state that documentation should reside in
                                                        the most appropriate section and duplication of documents
                                                        should be avoided.
                                                        However, the Notice to Applicants mentions for section
                                                        2.7.6 “This section should include the table entitled Listing
                                                        of Clinical Studies, described in guidance for Module 5,
                                                        followed by all individual study synopses organised in the
                                                        same sequence as the study reports in Module 5.” This
                                                        seems to be not in line with the eCTD rules as this leads to
                                                        duplication of the document.

CR-20091116-   Caroline Keller,   NtA Volume 2B         Could EMEA clarify how the supportive documentation of                                                        Duplicated         None                                  N/A                  Refer to CR-20080909-01.
04             Novartis Pharma                          RMPs should be handled? The Notice to Applicant for
                                                        section 1.8.2 states that the section should be stand-alone,
                                                        which seems to be not in line with the eCTD rules this may
                                                        lead to duplication of supportive documents (e.g. literature
                                                        references in 1.8.2 and 5.4 or study protocols in 1.8.2 and
                                                        5.3).

                                                        The eCTD rules state that documentation should reside in
                                                        the most appropriate section (e.g. literature references in
                                                        3.3, 4.3 or 5.4 as appropriate) and duplication of documents
                                                        should be avoided.
                                                        However, the Notice to Applicants mentions that “The RMP
                                                        should be presented in a stand-alone format (separate
                                                        volumes in paper) allowing circulation to, and evaluation by
                                                        pharmacovigilance and risk management experts. It should
                                                        be accompanied by other relevant documents such as study
                                                        protocols, where applicable.”
                                                        This seems to me conflicting as this can lead to duplication
                                                        of documents and therefore increased life-cycle
                                                        maintenance issues.

CR-20100504 Sibulle               EU Module 1           The Style Sheet for EU M1 (version 1.4) displays the wrong       Duplicate to CR-20010408                     Duplicated         None                                  N/A                  Refer to CR-20080909-01.
            Teuchmann,            (version 1.4) style   information in the envelope for the Hungarian authorities
            Exalon GmbH           sheet                 (veterinary is associated with OGYI).
                                                                                                                                                                    EU eCTD Specification Change Requests
      #           Requestor        Specification                            Description                                         Comments   Status          Action               Group Where Action           Notes
                                   Component                                                                                                                                    is Sitting
CR-20100607- Sandra Taylor, J&J EU eCTD               Criterion No. 35 states “EU M1.3 file name convention is   not advanced              CCB 9/2010 -     None                ask Harmonisation Group if
     01                         Validation Criteria   followed”. “EU M1.3” is ambiguous as this could mean the                             Duplicate to CR-                     they agree
                                v2.1 April 2009       EU Module 1 Specification version 1.3 or Module 1.3.                                 20091217-01
                                                      Product Information. We assume this relates to the EU
                                                      Module 1 Specification, if so by including the version
                                                      number, the criterion quickly becomes outdated.
                                                                                                                                                                                   EU eCTD Specification Change Requests
      #          Requestor         Specification                             Description                                           Comments                   Status      Action               Group Where Action   Notes
                                   Component                                                                                                                                                   is Sitting
QA-20070628- Thierry Le Ridant,                      For an association of two active substance (eg Paracetamol Sep-07 Requested to be withdrawn and Withdrawn            None                 N/A                  No further action required by EU with regard
     03      Ethypharm                               / dextroproxifen), what is the best practice : duplicate <atc> resubmitted as a CR (subsequently                                                               to EU M1 v1.4
                                                     and <inn> element ?                                            submitted as CR-20070718-01)

QA-20070813- Phyllis Thomas,                         In Europe (and with the current ICH M2 eCTD specification),      Aug-07 Requested to be withdrawn due Withdrawn      None                 N/A                  No further action required by EU with regard
     01      AstraZeneca                             does the applicant need to update attributes in the eCTD         to an error. To be resubmitted after                                                          to EU M1 v1.4
                                                     backbone during the life an application?                         correction of error. (Resubmitted as
                                                     Further detail included in original question.                    Q&A-20070816-01)

CR-20080129- Geoff Williams,      EU Module 1        A previously submitted CR (20070309-01) proposed the             Feb 08: New change request to be        Withdrawn   None                 N/A                  Related to CR 20090506 which will be
     02      Roche                DTD, eu-           prohibition against the use of “common” as an acceptable         submitted by EFPIA proposing a                                                                implemented in EU M1 v1.4 (clarificaiton of
                                  envelope.mod and   country identifier in the EU Module 1 envelope. This CR          'softened' approach where the country                                                         the use of 'common').
                                  Specification,     seeks to clarify the use, or otherwise, of the country           identifier 'common' can be used in
                                  v1.2.1             identifier “ common” for content files in the EU Module 1.       certain circumstances.

                                                     Currently, no clear guidance exists about the correct use of     May 2009: related to CR-20090506 from
                                                     the country identifier “common” when creating an EU              Bil Ali of Shire.
                                                     Module 1 eCTD, particularly in relation to the application of
                                                     this country identifier to content files. This has led to an
                                                     inconsistency in usage of the value for the country attribute.

                                                     A country identifier is used for content included in sections
                                                     of Module 1 that can contain country specific content. The
                                                     original intent of the “common” country value was to provide
                                                     some means of identifying content that was used submitted
                                                     in a section that can contain country specific information
                                                     but, in this particular submission, is reused by several
                                                     countries.

                                                     Propsal:The submitter of this CR proposes completely
                                                     removing the country identifier “common” from the list of
                                                     acceptable country identifier values. Specific guidance
                                                     should be included about to how to manage content that is
                                                                                                                                                                                                                                     EU eCTD Specification Change Requests
       #           Requestor         Specification                                 Description                                                   Comments                          Status                                    Action                                       Group Where Action   Notes
                                     Component                                                                                                                                                                                                                            is Sitting
     0007       IABG (T.            eCTD EU Module      eCTD should take into consideration the ISO standard ISO/PRF             This was referred to ICH where it was             Rejected                                  None                                         N/A                  No further action required by EU with regard to
                Bergsteiner)        1 Specification     19005-1 ( PDF/A) for long-term readibility of PDF documents.             concluded that PDF/A does not support the                                                                                                                     EU M1 v1.4
                                                                                                                                 review process for eCTDs. Response issued
                                                                                                                                 as ICH eCTD Q&A 47.

 20060627-03    Andrew Marr, GSK EU Module 1 DTD        When to submit Module 3 updates as part of responses to questions        16-12-2008 eCTD Interlinking: The module 3        Accepted - refer to Interlinking Group;   Produce an NTA CTD Q&A detailing the         Interlinking Group
                                 and Specification,     with an eCTD                                                             documents should be handled in the same way       7/2010 A. Marr to follow-up if Q&As       guidance to submit only the final agreed
                                 v1.2                                                                                            that the SPC is currently handled in eCTD -       address this and raise at Interlinking    version of the M3 documents in the eCTD.
                                                        Currently with a paper submission there is the possibility of            only the final agreed versions of the             the potential to closed                   (This will set a precedent for an eCTD Q&A
                                                        submitting a response to a question which may contain a proposal         documents should be submitted at (or just         9/2010 - discussed at Interlinking; A.    and any appropriate guidance change).
                                                        (e.g. a change to the specification) and when that is found to be        before) the end of the procedure. The interim     Marr actioned                             9/2010 - A. Marr to draft a more detailed
                                                        acceptable by the regulators the revised Module 3 content can be         versions should not be exchanged in the           10/2010 - Interlinking Group -            Q&A with some examples
                                                        submitted. With an eCTD is it always expected that the Module 3          eCTD - they should be exchanged as                Proposal agreed. Q&A to be finalised.     10/2010 - Proposed Q&A added to tracking
                                                        section is updated at the time of submitting the response or can this    communications outside the eCTD.                  CCB 11/2010 - It seems that there is      table.
                                                        also be delayed until it is known that the response is acceptable?       March-09: Options for Q&A have been drafted       overlap between this CR and               CCB 12/2010- Collaboration between A.
                                                                                                                                 and are to be reviewed by the Interlinking        proposed Q&A and the CR                   Marr and K. Menges to address Interlinking
                                                        Draft response: At key stages of procedures there is need for rapid      Group.                                            20100707 that was actually rejected.      comments and identify a suitable path
                                                        turnaround of submissions and in order to meet deadlines then            9/2010 - Reviewed options previously              Will ask requesters to work together.     forward.
                                                        documents may be sent to reviewers via Eudralink, outside of the         developed by A. Marr; he is actioned to draft a   Potentially withdraw the 2 CRs and        CCB 2/2011 - Move to closed [rejected].
                                                        eCTD, but must be followed up with submission to the eCTD.               more detailed Q&A with some examples              combine them into a new CR
                                                        Only the responses to questions in Module 1 documents need be            Interlinking agreed on following :                CCB 12/2010 - see actions
                                                        provided outside of the eCTD. It is acceptable to delay submission of 10/2010 - At key stages of procedures there is       12/2010 - Interlinking said to move to
                                                        Module 3 documents until the responses have been agreed but the          need for rapid turnaround of submissions and      closed [rejected] as this is addressed
                                                        final versions must be submitted to the eCTD before the completion       in order to meet deadlines then documents         in the Best Practice Guide which
                                                        of the procedure, with a new sequence number.                            may be sent to reviewers via Eudralink,           states not to use the eCTD backbone
                                                                                                                                 outside of the eCTD, but must be followed up      for draft documents.
                                                        EFPIA eCTD TG Comment: Not sure the answer is quite right, talks with submission to the eCTD. Only the
                                                        about tight timelines in MRP, whereas the question does not.             responses to questions in Module 1
                                                        What if it's not rapid turnaround, but you‟re unsure if your proposal    documents need be provided outside of the
                                                        for an m3 document is going to be agreed? Do you put the doc in          eCTD. It is acceptable to delay submission of
                                                        m3, or keep in M1 until agreed? Answer suggests you would                Module 3 documents until the responses have
CR-20070130- Shy Kumar,             eCTD EU Module      Eudralink it, but this might not be appropriate. Also don‟t understand, been agreed but the to specification. No re-
                                                        The EU Module 1 Specifications, version 1.1, provided a description Mar-07 No change final versions must be                Rejected                                  None                                         N/A                  No further action required by EU with regard to
     01      Datafarm               1 specification     of the field "submission-description" in the envelope, including a size instatement of max. 50 character field length.                                                                                                                 EU M1 v1.4
                                    v1.2.1              limitation set to 50 characters.                                         Gain practical experience with no limitation.
                                                        The EU Module 1 Specifications, version 1.2.1, has removed the
                                                        information on the field size limitation. There is no indication whether
                                                        the limitation still applies or not.
                                                        Note: A similar question has been asked in the context of the eCTD
                                                        on the length of the "title" element(Change Request 750). The initial
                                                        answer was to limit the 1024 bytes. However during one of the last
                                                        meetings (June 2006), it has been decided to remove the size
                                                        limitation, and to request concise titles.

CR-20070215- Ashley Birch,          ICH eCTD Q&A 40 ICH eCTD Question Number 40 asks whether it is acceptable to                                                                   Rejected                                  Discussed at ICH M2, see ICH tracking        N/A                  Clarify in EU M1 v1.4 the use of PDF v1.4, if
     01      AstraZeneca                            submit PDF V1.4 files across all regions. Although the answer given                                                                                                      sheet for details of outcome.                                     any decision has been reached at ICH level.
                                                    is in the affirmative, it actually goes much further than mere
                                                    „acceptability‟ by appearing to make V1.4 mandatory for eCTDs.
                                                    Shouldn‟t V1.4 be „acceptable‟ or perhaps „preferred‟ (if justified)
                                                    rather than „mandatory‟?


CR-20070718-01 Thierry Le Ridant,   eCTD EU Module      In the Envelope, in the case of an association of 2 active substances,   Nov-07 Was referred to eCTD Interlinking         Rejected                                   None                                         N/A                  No further action required by EU with regard to
               Ethypharm            1 specification     there is no link between the <inn> element and the <atc> element.        Group "No changes required – Because there                                                                                                                    EU M1 v1.4
                                    v1.2.1              We suggest to regroup them into an <active> element which will           is no one to one relationship between
                                                        permit to identify the link between atc and inn.                         substance and atc codes. The codes relate to
                                                                                                                                 the indication of the product."
                                                                                                                                 Subsequent research shows this may not be
                                                                                                                                 correct.
                                                                                                                                 June 2008: eCTD Interlinking: ATC code left
                                                                                                                                 in EU M1 v1.3
                                                                                                                                 Dec 08: Interlinking Group - there is definitely
                                                                                                                                 no link between the substance and the
                                                                                                                                 atc.Consideration of whether to remove the atc
                                                                                                                                 from the eCTD envelope, in anticipation of the
                                                                                                                                 eAF which will enable use of structured meta-
                                                                                                                                 data on the submission (including the atc if
                                                                                                                                 necessary).
                                                                                                                                 March-09 : Close this change request. Open
                                                                                                                                 new change request for deletion of ATC code
                                                                                                                                 from EU Module 1 specification. Ensure that
                                                                                                                                 requirements for ATC code use are defined
                                                                                                                                 and progressed within eAF project.


CR-20070814- Ann Verhoye,           ICH CR 1550         Request to re-open change request 1550: this change request is           Sep-07 Examples in two provided annexes           Rejected                                  None                                         N/A                  No further action required by EU with regard to
     01      FAMHP, Belgium                             closed mentioning that all filenames in module 2.3 and 3 will be         were reviewed. No consensus on proposal                                                                                                                       EU M1 v1.4
                                                        mentioned in italics: this means that no filename check is possible,     Rejected
                                                        and no standard for filenames could be introduced. FAMHP, has
                                                        made a proposal in order to foresee the possibility for multiple
                                                        documents to be submitted within module 3, so to allow granularity,
                                                        and to keep filename standards as well, therefore, the FAMHP
                                                        requests to reopen this CR and to have a look at the FAMHP
                                                        granularity proposal in order to foresee variable parts in the filenames
                                                        and to maintain fixed components as a standard. First reactions form
                                                        the national IT workgroup in Belgium were very positive.
                                                                                                                                                                                                                           EU eCTD Specification Change Requests
      #          Requestor         Specification                                  Description                                                   Comments                         Status                             Action                     Group Where Action   Notes
                                   Component                                                                                                                                                                                                   is Sitting
CR-20071001- Deanna Murden,                            How should sponsors manage summary documents in Module 2                 Nov-07 Referred to ad hoc group for             Accepted - refer to Harmonisation                             N/A                   No further action required. Already covered in
     01      i3Logic                                   over the lifecycle of an application?                                    discussion and position                         Taskforce;                                                                          the EU harmonised eCTD guidance
                                                                                                                                                                                7/2010 CCB recommends rejecting,
                                                                                                                                                                                not needed




CR-20071009- Hans van             eCTD EU Module       Guidance is needed on how to maintain the lifecycle of Section 1.6       Nov-07 Referred to ad hoc group for             Accepted - refer to Harmonisation                             N/A                   No further action requried. Enough covered by
     01      Bruggen,             1 specification      Environmental risk Assessments, using the operations new, append         discussion and position                         Taskforce;                                                                          general guidance in the EU harmonised eCTD
             eCTDConsultancy      v1.2.1               replace and/or delete.                                                                                                   7/2010 CCB recommends rejecting,                                                    guidance.
             B.V.                                      Further information included in the original change request                                                              not needed




CR-20080129- Geoff Williams,      EU M1 stylesheet     The current stylesheet displays the full structure of the Module 1,                                                      Rejected                            None                      N/A                   No further action required by EU with regard to
     01      Roche                                     whether the displayed sections have content or not. This is a little                                                                                                                                         EU M1 v1.4
                                                       confusing as it gives the impression of much more information than is
                                                       really present. In addition, some sections are mutually exclusive and                                                                                                                                        (Include a note in the Spec about the approach
                                                       others only apply for particular procedure types.                                                                                                                                                            of the style-sheet, i.e. to display all the entries in
                                                       The display of the complete structure is not consistent with the                                                                                                                                             the ToC even if there is no content attached to
                                                       behaviour of the ICH stylesheet, which only displays sections that                                                                                                                                           some sections).
                                                       have content.
                                                       Proposal: Change the stylesheet so that it only displays sections that
                                                       have content.

CR-20080514-     Anne Mieke    EU Module 1          Since sequence numbers do not have to be used in sequential order           The Cover Letter and tracking table if            Rejected                          None                      N/A                   No further action required by EU with regard to
03                Reijnders,   Specification v1.2.1 it would be beneficial to add the submission date back into the EU          appropriate should be used to track the date - it                                                                                   EU M1 v1.4
               eCTDConsultancy                      M1 envelope information.                                                    is not useful ot have it in the envelope.

CR-20080627 NMs Nadine            EU M1                As a manufacturer for plasma products, CSL have eCTDs for              Article 61(3) exists as a submission type in the Rejected                             None                      N/A                   No further action required by EU with regard to
            Schwarz, CSL          Specification v1.3   products which are registered under the Central Procedure and the      EU M1 specification v1.3                                                                                                              EU M1 v1.4
            Behring AG                                 Mutual Recognition Procedure. For either procedure, the CMD(h)
                                                       STANDARD OPERATING PROCEDURE PROCEDURE FOR
                                                       ARTICLE 61(3) CHANGES TO PATIENT INFORMATION (Rev. 1,
                                                       July 2007) is applicable. By this procedure, administrative changes to
                                                       the product information, such as corrections of typographical errors,
                                                       may be notified to EMEA or RMS instead of submitting a variation.
                                                       If this is done for an existing eCTD, there is no adequate submission
                                                       type defined in the Module 1 Specification to describe this
                                                       submission.


CR-20090701- Thierry Le Ridant,   EU M1                In eCTD the sequence folder (0000) is included in the "top level         Discussed by CR sub group 20091210              Rejected                            None                      N/A                   Guidance on this already exists in Annex II of
     01      Ethypharm            specifciation 1.3    folder" (ICH eCTD 3.2.2 page 6-1) The ICH guideline recommends                                                                                                                                               the EU M1 v1.4 Annex.
                                  &                    to consult regional guideline but currently there is not any naming
                                  Guidance for         recommendation.
                                  Industry on          In case of MRP/DCP should we use the MR/DCP number or
                                  Providing            national case number ?
                                  Regulatory           Should we use only the procedure number or a combination of
                                  Information in       inn+strength+procedure number ?
                                  Electronic Format:   In a national procedure, what is the wish of each member states?
                                  eCTD Applications    How to manage multiple strength eCTD applications?
                                  Version: 1.0 May
                                  2009


CR-20090909 Anne Mieke            EU M1 v1.4 - Page Page 8 of the written specification, second bullet point, refers to         Recommendation in CR form: Keep the annual Rejected                                 None                      N/A                   Proposal rejected as the Annual Report should
            Reijnders, eCTD       8 and 14 of the       “group number/ periodic report number” . Does periodic report here      report which is submitted for one product                                                                                           be defined as a grouped variation
            Consultancy           written specification mean annual report?                                                     separate and simple: no additional mode‟s or                                                                                        submission.Term 'Periodic Report' should be
                                                        The annual report, type IA notifications for one product, is not        grouping numbers are necessary. It is a                                                                                             removed from the EU M1 v1.4 specification.
                                                        considered “grouping” in the EU Procedural Guideline Annex of           regular regulatory activity that can be handled                                                                                     This action is captuured in CR 20091210.
                                                        February 2009.                                                          by the eCTD.
                                                        Moreover, for annual report (or for any other grouping per product)
                                                        no additional numbers are needed, the submission could use the
                                                        regular variation and sequence number.
                                                        Page 14, table, specifies that the mode grouping should be used for
                                                        periodic reports, this seems superfluous as explained above.
                                                                                                                                                                                                  EU eCTD Specification Change Requests
     #          Requestor       Specification                                   Description                                                     Comments                       Status      Action                     Group Where Action   Notes
                                Component                                                                                                                                                                             is Sitting
CR-20090909- Anne Mieke        EU M1 v1.4           According to the draft EU Procedural Guideline Annex of February       Recommended in CR form: Delete the            Rejected          None                      N/A                   Discussed by CR subgroup 20091210.
     04      Reijnders, eCTD                        2009 the variation regulation is set up to reduce the number of        requirement for a consolidation sequence from                                                                   Regulators strongly advise consolidation
             Consultancy                            variations and administrative burden for Agencies and Industry. This the M1 annex v1.4                                                                                                 sequences and industry agree. Already done for
                                                    to enable competent authorities to focus on those variations that                                                                                                                      parallel variations. Consolidation sequences are
                                                    have a genuine impact on quality, safety or efficacy. Looking at the                                                                                                                   a valid part of the lifecycle. Reject CR.
                                                    “translation” of EC 1234-2008 into eCTD the administrative burden
                                                    seems only to increase.
                                                    An example is the consolidation sequence, mentioned on page 17 of
                                                    EU M1 Annex v1.4: A consolidation sequence should always be
                                                    sent at the end of the procedure, reflecting the approved scope of the
                                                    variation.

                                                    The table on page 17 of EU M1 Specifications v1.4 describes a final
                                                    sequence in the regulatory activity with updated agreed product
                                                    information. This is already common practise if labelling is involved in
                                                    the variation. However the requirement of an additional sequence
                                                    submission at the end of all variations (per MRP/DCP and per
                                                    country)seems to increase the administrative work (and costs) at
                                                    both sides. As long as eCTD is based on one-way communication
                                                    the approval or any other information from the authorities is not part
                                                    of the eCTD.
CR-20090909- Kevin Wing,       EU M1 v1.4, Page     Changes to (1) DTD and (2) specification in relation to the              See details in CR form                            Rejected    None                      N/A                   Misunderstanding of the specification - reject
     07      eCTDConsultancy   14 - 15 of the       <submission> “mode” attribute, the <submission><number> element                                                                                                                        CR.
                               written              and its value and the <tracking><number> element and its value.
                               specification.
                               Page 44 of the
                               DTD.
                               Pages 16 – 20 of
                               the specification
                               annex.

CR-20090909- Hans van          EU M1 v1,4, Page     Missing Files - The CTD guidance addresses how to justify missing          Recommendation on CR form: The correct           Rejected   None                      N/A                   Discussed in subgroup 20091210. Guidance is
     09      Bruggen,          7 of the             data that should be available for a proper evaluation of the quality,      wording should be:                                                                                          considered already clear.
             eCTDConsultancy   specification        safety and efficacy of the drug. The eCTD guidance should only add         “Handling of Empty or Missing eCTD Sections
             B.V.                                   guidance to the nodes in a ToC that do not have leafs, because             Note that placeholder documents highlighting
                                                    these are irrelevant to for the proper evaluation of the quality, safety   'no relevant content' should not be placed in
                                                    and efficacy of the drug.                                                  the eCTD structure, as these would create a
                                                                                                                               document lifecycle for non-existent
                                                                                                                               documents, and unnecessary complication
                                                                                                                               and maintenance of the eCTD.
                                                                                                                               The justification of absence of scientific data,
                                                                                                                               is irrespective of the dossier format (paper
                                                                                                                               CTD or eCTD) and should be provided in the
                                                                                                                               relevant Quality Overall Summary and/or Non-
                                                                                                                               Clinical/Clinical Overviews (Module 2.3, 2.4,
                                                                                                                               2.5).




CR-20090909- Hans van          EU M1 v1.4, Page The use of the terms node extensions and subfolders is often                   Recommended on CR form: Either clearly          Rejected    None                      N/A                   Reject. The specification should not be changed
     11      Bruggen,          9; Section on Node confusing for users of the eCTD. It should be made clear what the            address the particulars related to subfolders                                                               based on differing interpretations from vendors.
             eCTDConsultancy   Extensions         differences are, before mentioning these two items together in a             and node extension as described above, or                                                                   Node extensions meet important business
             B.V.                                 bullet in Section Node Extensions on Page 9.                                 prohibit the use of node extensions and                                                                     needs. The STF is built to meet US regional
                                                  Furthermore, the use of node extension is not sufficiently                   encourage the STF. Note that not all items                                                                  requirements and submissions cannot and
                                                  investigated in interoperability tests across multiple software tools.       listed in an STF are to be included.                                                                        should not be fully re-used across regions in
                                                  From the FDA it is clear that not all tools show the node extensions                                                                                                                     any case.
                                                  as intended and switching from one tool to the other might even
                                                  result in an inability to maintain lifecycle on leafs located in a node
                                                  extension.
                                                  Finally, the main reason for encouraging the use of node extensions
                                                  is eliminated by adopting the STF, developed up to Step 4 by the ICH.
                                                  This change request is either to clearly address the particulars
                                                  related to subfolders and node extension, or to prohibit the use of
                                                  node extensions and encourage the STF


CR-20090909- Hans van          EU M1 v1.4,          The written specification as well as Appendix 2 provide examples of        Recommended on CR form: Remove the              Rejected    None                      N/A                   Discussed in CR subgroup 20091210. Reject.
     12      Bruggen,          Examples on Page     file names. However, the examples of the variable text are confusing.      examples it-form-annex1.pdf and common-                                                                     The leaf title should be used to identify the file,
             eCTDConsultancy   10 of the written    As a general rule, the variable parts should be meaningful. common-        form-annex12.pdf from respectively Pages 10                                                                 rather than the file name, if the eCTD is beng
             B.V.              specification        form-pheurcertificate.pdf and pt-form-proofpayment.pdf do, but it-         and 21.                                                                                                     used properly. The file naming convention and
                               concerning           form-annex1.pdf and common-form-annex12.pdf do not. The annex                                                                                                                          folder structure should not be relied upon. The
                               Directory/File       numbering is related to the application form for an initial MAA and                                                                                                                    examples given in the specification are
                               structure and Page   line extension only. Hence, proof of payments, certificates of                                                                                                                         considered adequate and should not be
                               21 Row 8 of          suitability related to variations can never be considered a numbered                                                                                                                   changed.
                               Appendix 2           annex. Therefore, a consistent use of descriptive terms is considered
                                                    to contribute to a consistent and unambiguous guidance.
                                                                                                                                                                                                                                    EU eCTD Specification Change Requests
     #          Requestor       Specification                                   Description                                                    Comments                            Status                                   Action                                          Group Where Action    Notes
                                Component                                                                                                                                                                                                                                   is Sitting
CR-20090909- Anne Mieke        EU M1 v1.4,       For both grouping and worksharing of variations page 17 and 18 of           Discussed in CR subgroup 20091210. A                  Accepted - refer to eCTD Interlinking    When M1 specification is updated                Interlinking Group
     06      Reijnders, eCTD   Annex p17 and 18. EU M1 Annex v1.4 state that: “ Note that for each affected                  template for a cover letter exists, and this          Group                                    9/2010 - Need to resolve concerns from
             Consultancy                         marketing authorisation, a separate eCTD submission must be                 indicates that it is country-specific. EMA            7/2010 - Follow-up with Interlinking     France and Spain re national application
                                                 provided”.                                                                  however seems to be of the opinion that the           Group                                    forms
                                                 In addition page 19, 2nd paragraph states “The ICH eCTD v3.x                cover letter should be identical for all countries.   9/2010 - Interlinking discussed;
                                                 specification                                                               Guidance does exist for both AF and cover             remains open. Owner of Module 1
                                                 only allows the submissions of information relating to a single             letter. Take to Interlinking for clarification.       specification is TIGes with EMA as
                                                 marketing authorization”                                                    7/2010 - This would be resource saving                rapporteur
                                                                                                                             10/2010 - Interlinking agreed on following :          10/2010 - Interlinking - CR rejected.
                                                    However, EC 1234-2008 article 7(2) (b) refers to a single notification   CR is rejected.
                                                    or a single application in case of grouping. According to the draft EU   This CR was submitted before the final
                                                    Procedural Guideline Annex of February 2009 one cover letter and         documentation on the new variation regulation
                                                    application form should be used.                                         was published.
                                                                                                                             According to the published (guidance)
                                                    Could you clarify and confirm the use of identical cover letters and     documentation, it is clear that for a grouped or
                                                    application forms for the separate eCTD‟s?                               Worksharing variation, one common
                                                                                                                             Application Form, which lists all affected MA's
                                                                                                                             is submitted.
                                                                                                                             For the cover letter the CMD(h) Best Practise
                                                                                                                             Guide on Variations refers to the use of a
                                                                                                                             common cover letter for grouping of multiple
                                                                                                                             MA's.

CR-20091015 Katrin Spaepen,    Best Practice        Can the eCTD sequence serving as the baseline be used as a               Proposed solution:                                    Accepted - refer to eCTD Interlinking    Produce additional guidance on the use of  Interlinking Group
            Comply Services    Guideline            sequence to harmonise formats (e.g. paper to eCTD format) but also       To use the baseline submission not only to            Group                                    eCTD metadata in an eCTD 'baseline'
                               “Guidance for        as a sequence to harmonise procedures (e.g. DCP to MRP)?                 harmonize to the eCTD format but also to              7/2010 - Interlinking Group concluded    submission for changing in repeat use from
                               Industry on                                                                                   harmonize the procedures and move from the            in 15 Dec 09 to reject and close         MRP to DCP. Guidance to go into the eCTD
                               Providing                                                                                     DCP to the MRP procedures for Member                                                           Best Practice Guide for MRP/DCP. (KG)
                               Regulatory                                                                                    States MS1 to MS5 and to number the
                               Information in                                                                                baseline sequence 000X (in this example                                                        Check existing baseline guidance in eCTD
                               Electronic Format:                                                                            0010). In practise, this means that the Module                                                 harmonised guidance to ascertain if it is
                               eCTD electronic                                                                               1 information as used for an MRP will be                                                       sufficient. (CWH)
                               Submissions                                                                                   applied for MS1 to MS5 in the baseline                                                         If necessary, clarify in eCTD harmonised
                                                                                                                             submission and that the so called baseline                                                     guidance that old NTA format Parts 3 and 4
                                                                                                                             submission equals the “sequence 0005”                                                          should also be converted to eCTD if they are
                                                                                                                             including the country specific information as                                                  submitted electronically. (KG)
                                                                                                                             per Chapter 7 of the NTA as in the example on
                                                                                                                             page 10 of the CMDh Best Practise Guide on                                                     Assigned to GW and KG (Interlinking
                                                                                                                             the use of the eCTD in the MPR and DCP dd.                                                     Group).
                                                                                                                             April 2008.

                                                                                                                             Discussed at TIGes/NtA Interlinking Meeting
                                                                                                                             20/10:
                                                                                                                             Agreement in principle to use the baseline to
                                                                                                                             harmonise the procedures using the baseline.
                                                                                                                             Guidance is needed on this, on how to use
                                                                                                                             eCTD metadata in repeat use. The Procedure
                                                                                                                             Type element at least should change from
                                                                                                                             DCP to MRP.
                                                                                                                             7/2010 - Discussed at Interlinking 15 Dec;
                                                                                                                             conclusion that guidance was clear enough on
                                                                                                                             this matter


CR-20100128 Anita Anand        eCTD MRP/DCP         The Harmonised eCTD guidance (v1.0) Guidance for Industry on             Discussed by trial CCB 20100517                       Accepted - referred to eCTD              Incorporate change in release plan for next      Interlinking Group
            Phadnis, Educe     Tracking Table       Providing Regulatory Information in Electronic Format: eCTD              7/2010 - XML table will only support                  Interlinking Group 17 May 2010           version of tracking table; it is deferred to the
            Solutions          specification        electronic Submissions, section 2.9.3 recommends the use of the          MRP/DCP NEED date discussed                           7/2010 - Rejected by Interlinking        Interlinking group whether the Requestor
                                                    tracking table for national submissions. However, there is only an                                                             Group                                    needs to provide additional specifics in order
                                                    XML specification for the table for MRP/DCP and it cannot be used                                                                                                       to adopt the changes requested
                                                    for national submissions, for example a CMS is required.

CR-20100707 Klaus Menges,      CMDh BPG,            BPG on DCP allows to submit draft versions of the applicant              Guidance needed on how to best deal with              CCB 9/2010 - Referred to Interlinking    Need feedback on whether this goes to          Interlinking Group
            BfArM              TIGes eCTD           response document (ARD). This can be in case of eCTD a formal            drafts, as up to now nothing is said to this type     group                                    Interlinking or CMDh; consider if software
                               submission           sequence but not entirely finalised. For finalisation a second           of submission in the TIGes eCTD submission            10/2010 - Interlinking agreed on         vendors should be consulted for feasibility of
                               Guidance             sequence may be necessary. Two options to deal with are possible:1.      guidance.                                             following:CR is rejected.                the two options suggested.
                                                    It will not be counted as a formal sequence and not loaded to the        10/2010 - Interlinking agreed on following: CR        CCB 11/2010 - It seems that there is     12/2010 - Interlinking said to move to closed
                                                    NCA eCTD reviewing tool (but full support for assessors is not           is rejected.                                          overlap between this CR and the CR       [rejected] as this is addressed in the Best
                                                    available) 2. It is counted as a formal sequence and the finalising      The CMD(h) BPG for the use of eCTD in                 20060627-03 and associated               Practice Guide which states not to use the
                                                    sequence will be submitted thereafter. Both sequences need to be         MRP/DCP defines that draft responses are              proposed Q&A. Will ask requesters        eCTD backbone for draft documents.
                                                    submitted to CMSs or the draft need to be overwritten by the final       outside the scope of eCTD.                            to work together. Potentially withdraw   1/2011 - Move to closed [rejected].
                                                    version of the same sequence. A further outline is attached.             Follow-up: EFPIA eCTD TG suggests                     the 2 CRs and combine them into a
                                                                                                                             handling in the NCA business process                  new CR
                                                                                                                                                                                   12/2010 - see CR-20060627-03
                                                                                                                                                                                   Action
                                                                                                                                                                                   CCB 2/2011 per Interlinking, move to
                                                                                                                                                                                   closed [rejected]
                                                                                                                                                                                         EU eCTD Specification Change Requests
     #           Requestor      Specification                             Description                                         Comments                 Status     Action                                         Group Where Action Notes                                           eAF Update (Philippe/Leigh)
                                Component                                                                                                                                                                        is Sitting
    0002      Sandoz (Ron de   Application Form   The EAF does not allow for the form to be combined for all                                           Deferred   Referred to NtA with MRFG                      eAF                No further action required - questions should   EFPIA eCTD TG comment:
              Boer)                               member states during MRP subm. For a paper based subm                                                           representatives.                                                  be addressed as part of the electronic          Lincoln/Philippe didn't respond to this one for some
                                                  this combined AF has been requested by some and has been                                                        R. de Boer to split the CR into those points                      application form development.                   reason.
                                                  accepted by all EU member state agencies. This change                                                           that are nice to have and those which are                                                                         Suggest closing as eAF has been developed far
                                                  request is made to enable the AF to be used during MRP                                                          essential requirements                                                                                            further than original eAF-new version. Extended
                                                  submissions. Some of the requests made below are suitable                                                                                                                                                                         Testing/Piloting should cover examples such as
                                                  for none MRP subm as well.                                                                                                                                                                                                        these to ensure that the eAF works as expected.
                                                  Generic apps - It should be possible to include reference                                                                                                                                                                         Recommend retesting to make sure they are
                                                  medicinal products for multiple MSs. In case of an MRP this                                                                                                                                                                       covered; completion will be date of the project
                                                  needs to be filled in for each MS, because the reference                                                                                                                                                                          completion
                                                  product marketed in each MS is different. This change is
                                                  relevant for MRP only.
                                                  It should be possible to include multiple medicinal products
                                                  used in the BE study.
                                                  All submission types. Proposed dispensing/classification - It
                                                  should be possible to select both “subject to medical
                                                  prescription” and “not subject to medical prescription”.
                                                  It should be possible to include multiple marketing
                                                  authorisation holders.
                                                  CP&MRP It should be possible to include multiple persons
                                                  authorised for communication after authorisation.
                                                  It should be possible to include multiple qualified persons for
                                                  pharmacovigilance .
                                                  It should be possible to include multiple persons responsible
                                                  for
                                                  scientific services.

20060914-01   Aziz Diop,       eAF DTD and style It is mandatory in the DTD to choose an option in the                                                 Deferred   Refer to eAF project                           eAF                No further action required - questions should   Philippe's response:
              AFSSAPS          sheet             centralised procedure between (mandatory scope, optional                                                                                                                           be addressed as part of the electronic          As requested by CR-20060914-01, the DES 2.0
                                                 scope and Generic of a Centrally Authorised Medicinal                                                                                                                              application form development.                   business rules impose a selection of only one of
                                                 Product). Example of a product                                                                                                                                                                                                     the following options:
                                                 “Aluvia film-coated tablets”                                                                                                                                                                                                       ����« Mandatory scope » (Article 3(1))
                                                 200mg of lopinavir/50mg of rotonavir                                                                                                                                                                                               ����« Optional scope » (Article 3(2))
                                                 A CHMP scientific opinion : Article 58 Regulation (EC) N°                                                                                                                                                                          ����« Generic of a Centrally Authorised Medicinal
                                                 726/2004                                                                                                                                                                                                                           Product » (Article 3(3))
                                                 Date acceptance by WHO : 24-05-2006
                                                                                                                                                                                                                                                                                    But the business rules also includes the following
                                                                                                                                                                                                                                                                                    rules:
                                                                                                                                                                                                                                                                                    - In case the of article 3.1 of regulation 726/2004
                                                                                                                                                                                                                                                                                    then only one of the following may be chosen:
                                                                                                                                                                                                                                                                                    ����Annex (1) (Biotech medicinal product)
                                                                                                                                                                                                                                                                                    ����Annex (3) (New active substance for mandatory
                                                                                                                                                                                                                                                                                    indications)
                                                                                                                                                                                                                                                                                    ����Annex (4) (Orphan designated medicinal product)

                                                                                                                                                                                                                                                                                    - In case of article 3.2 of regulation 726/2004 then
                                                                                                                                                                                                                                                                                    only one of the following may be chosen
                                                                                                                                                                                                                                                                                    ����Article 3(2)(a) (New active substance)
                                                                                                                                                                                                                                                                                    ����Article 3(2)(b) (Significant innovation or interest
                                                                                                                                                                                                                                                                                    of patients at Community level)
                                                                                                                                                                                                                                                                                    EFPIA eCTD TG rep comment:
                                                                                                                                                                                                                                                                                    Being Implemented, testing needed - Closure
                                                                                                                                                                                                                                                                                    pending completion of the project


CR-20070711- Alban Dhanani,    eAF-New v2.1       The current Application Form for New applications is not well                                        Deferred   Refer to eAF project                           eAF                No further action required - questions should   Philippe's response:
     01      AFSSAPS                              designed in terms of reporting of CMS involved in subsequent                                                                                                                      be addressed as part of the electronic          The notion of wave-number has been Implemented
                                                  waves in the case of a repeat use in the decentralised                                                                                                                            application form development.                   in the DES 2.0 the starting procedure has a wave-
                                                  procedure. The impact on the current eAF-New is even bigger                                                                                                                                                                       number = 0. The current procedure has the highest
                                                  since it is not possible to identify CMS for different waves                                                                                                                                                                      wave-number.
                                                  (wave number element missing) and a change to the dtd is                                                                                                                                                                          Wave-number=0 is only valid for Centralised,
                                                  needed to make it possible.                                                                                                                                                                                                       National, and decentralised procedure. N>0 is valid
                                                                                                                                                                                                                                                                                    for Mutual recognition procedure.

                                                                                                                                                                                                                                                                                    The concerned and reference member states shall
                                                                                                                                                                                                                                                                                    be mapped to their corresponding procedure ans
                                                                                                                                                                                                                                                                                    wave-number
                                                                                                                                                                                                                                                                                    EFPIA eCTD TG rep comment:
                                                                                                                                                                                                                                                                                    Being Implemented, testing needed - Closure
                                                                                                                                                                                                                                                                                    pending completion of the project
CR-20070714- Kevin Wing,       eAF New            The specification for the eAF-new does not specify the use of     Sep-07 Accepted for next           Deferred   Refer to eAF project                           eAF                No further action required - questions should   Philippe's response:
     01      eCTDConsultancy   specification      relative filepaths for the xlink:href attribute value             release of eAF-New specification                                                                                be addressed as part of the electronic          As Xlink is used only for presentation purpose, the
                                                                                                                                                                                                                                    application form development.                   DES does not provide a model to cover it.
                                                                                                                                                                                                                                                                                    Nevertheless, the model provides a field in the
                                                                                                                                                                                                                                                                                    model where an uri or url can be added. So far the
                                                                                                                                                                                                                                                                                    attachment concept is used to assess that the user
                                                                                                                                                                                                                                                                                    agreed he has added the document (annex).
                                                                                                                                                                                                                                                                                    EFPIA eCTD TG rep comment:
                                                                                                                                                                                                                                                                                    Being Implemented differently, testing needed -
                                                                                                                                                                                                                                                                                    Closure pending completion of the project
                                                                                                                                                                                    EU eCTD Specification Change Requests
     #          Requestor       Specification                          Description                                       Comments                 Status     Action                             Group Where Action Notes                                           eAF Update (Philippe/Leigh)
                                Component                                                                                                                                                       is Sitting
CR-20070816- Kevin Wing,       eAF-New v2.1     The specification for the eAF-new does not enable multiple      Sep-07 Accepted for next update   Deferred   Refer to eAF project               eAF                No further action required - questions should   Philippe's response:
     02      eCTDConsultancy                    meeting dates to be included for provision of CHMP scientific   to the specification                                                                               be addressed as part of the electronic          Is this the date provided in the rev9 of the
                                                advice (section 3.1) or for Member State scientific                                                                                                                application form development.                   Application new? If yes but one date per reference.
                                                recommendations (section 3.2)                                                                                                                                                                                      EFPIA eCTD TG rep comment::
                                                                                                                                                                                                                                                                   Being Implemented, testing completed - Closure
                                                                                                                                                                                                                                                                   pending completion of the project

CR-20070912- Jose Manuel       eAF-New v2.1     Orphan medicinal product information (section 1.2) applies to                                     Deferred   Referred to eAF project            eAF                No further action required - questions should   Philippe's response:
     01      Simarro, AEMPS,                    all types of procedures not only for centralised ones.                                                                                                             be addressed as part of the electronic          The DES 2.0 Model allows to have a section 1.2 for
             Spain                                                                                                                                                                                                 application form development.                   any type of procedure.
                                                                                                                                                                                                                                                                   EFPIA eCTD TG rep comment:
                                                                                                                                                                                                                                                                   Being Implemented, testing needed - Closure
                                                                                                                                                                                                                                                                   pending completion of the project
                                          EU eCTD Specification Change Requests
 #           Requestor               Specification
                                     Component
0001   Andrew Marr (EFPIA)      EU DTD v1.0,
                                Specification v1.0




0008   Spanish Agency of        eCTD EU Module 1
       Medicines (José Manuel   Specification
       Vidal Morales)




0009   GSK (Andrew Marr)        EU DTD v1.0,
                                Specification v1.0, EAF
                                v1.0
0010   EMEA (J. Rueda)      eCTD EU Module 1
                            Specification




0013   EFPIA (A. P. Marr)   eCTD EU Module 1
                            Specification
EU eCTD Specification Change Requests Implemented in EU M1 v1.1
                                   Description

         Experience is showing that when a number of lifecycle
         documents have been created it is not possible to know what
         each sequence is about with physically opening the sequence
         documents and reading the Cover Letter. Industry is already
         considering requesting the vendors to provide some additional
         description to assist in creation of the applications and we
         understand that at least the EMEA is adding a description to this
         Docubridge records. It would be logical to standardise on an
         additional attribute that the applicant can complete for there own
         records and that the agencies can make use of in their
         reviews.For example an applicant could use a simple description
         of „Excipient change‟ – against a Type II variation submission
         type. It this way a set of simple descriptions will be built up over
         time that will assist differentiation between sequence content
         without the necessity of opening a cover letter.

         EU Module 1 Specification:
         Element : m1-6-1-non-gmo
         Directory : m1/eu/16-environrisk/161-nongmo
         eCTD EU Backbone DTD - 1.0:
         Element : m1-6-1-non-gmo
         Directory : m1/eu/16-environrisk/161-non-gmo (without last
         hyphen)

         In the file eCTD EU Backbone DTD - 1.0 the directory must be
         named: m1/eu/16-environrisk/161-nongmo
         The New Medicines Legislation defines a new procedure for
         regulatory approval in Europe, that of the Decentralised
         Procedure. In the current eCTD envelope a picklist provides for
         the option of Centralised, Mutual Recognition or National.
         Decentralised needs to be added as an option. Likewise for the
         Electronic Application Form. These need to be in place for
         adoption of the new procedure in November 2005.
The inclusion of the PIM DES into EU Module 1 of the eCTD is
planned, as per the road map (DES 2.1), for December 2005.
This means that the current DES container will need to be re-
design in order to have a unique container for submitting PIM
in/outside eCTD and to minimise as much as possible changes
in the current eCTD EU Module 1 specifications.
To achieve this, the DES group has proposal for
implementation.Currently, when PIM is submitted inside eCTD,
EU M1 has two util folders, one in EU M1 level and another one
at the root level.
The PIM DES container has an util folder as well. The new PIM
container, scheduled for DES 2.1 DEC 05 will align with EU m1
structure (in/outside eCTD). With this new container there will be
a unique "util" folder in EU M1, the one already in there.
Note that the eCTD specifications define the location for DTDs
and style-sheets.
EU M1 specifications only contain screenshots with “util\dtd” and
“util\style”.
Full proposal in Change Request proposal


The structure of folders given in the EU Module 1 have
„Centralised‟, „Mutual‟ and „national‟ as folders between the root
folder and the sequence number. This was not intended as part
of the structure submitted in the eCTD.
Three representative folder structures are provided in the
specification to represent how folders and files should be placed
for each of the centralised, mutual and national procedures.
The folder structure includes „centralised‟, „mutual‟ or „national‟.
I do not believe that it was the intent that this folder, placed
between the root directory and the sequence number was
intended to be used in the submission itself. Recently, Belgium
has issued guidance for e-submission and refers to the EU
specification but they have been receiving examples where the
applicants have interpreted that the folder should be included.
This will cause problems later when eCTD are received (rather
than just e-subs in folder structures‟
uests Implemented in EU M1 v1.1
                             Comments                        Status              Action

            It may be possible to have an additional         Implemented in EU   Opened 19-09-2004
            attribute assigned to the submission type        M1 v1.1             Agreed 24-09-04
            „submission description‟. This could be either
            optional or mandatory dependent upon                                 Dec 05: Implemented
            submission type.                                                     in eCTD Spec v1.1 -
                                                                                 new element
                                                                                 'submission-
                                                                                 description' added to
                                                                                 envelope.




                                                             Implemented in EU   Dec 05: Implemented
                                                             M1 v1.1             in eCTD Spec v1.1,
                                                                                 cell 43 p.21




            Update the attribute values in the DTDs.         Implemented in EU   Dec 05: Implemented
                                                             M1 v1.1             in eCTD Spec v1.1
                                                                                 new attribute in
                                                                                 envelope.
An additional element “m1-3-1-pim-xxxx-y”       Implemented in EU     Dec 05: Implemented
will need to be created in EU M1 for            M1 v1.1               in eCTD Spec v1.1 -
accommodating the new PIM container when                              new element in 1.3.1
submitted within the eCTD




The folder structures should be clarified and the Implemented in EU   Dec 05: Implemented
„procedure‟ folders deleted. This should          M1 v1.1             in eCTD Spec v1.1
improve the clarity of the specification and
hence valid submissions.
                                    EU eCTD Specification Change Reques
 #           Requestor           Specification
                                 Component
0005   EMEA (T. Buxton)      eCTD EU Module 1
                             Specification




0006   Datafarm (S. Kumar)   eCTD EU Module 1
                             Specification
0015   PIM Core Team       eCTD EU Module 1
                           Specification




0016   PIM Core Team       eCTD EU Module 1
                           Specification




0017   Bernadette Billet   eCTD EU Module 1
       Liquent, Thomson    Specification
       Scientific
20060627-01   Geoff Williams, Roche   EU Module 1 DTD and
                                      Specification, v1.2




20060703-01   Geoff Williams, Roche   EU Module 1 DTD and
                                      Specification, v1.2




20060703-02   Geoff Williams, Roche   EU Module 1 DTD and
                                      Specification, v1.2
eCTD Specification Change Requests Implemented in EU M1 v1.2.1
                                 Description

      In the same way as the electronic application form permits
      information to be submitted using XML, so the PIM DES does the
      same for product information. The current EU Module 1
      specification permits PDF and RTF as formats for product
      information, but not XML. For administrative information, however,
      XML is permitted. Suggestion : Include XML as an accepted format
      for the “labelling text” item



      The specifications do not provide folder structure requirements for
      UTIL folder that includes STYLE and DTD folders. The screen
      shots are good and include a STYLE folder under UTIL folder
      under m1/eu. See page 25 to 29.Please note that the STYLE
      folder is already present under submission folder under UTIL
      folder e.g. eu12345/0000/util/style. In the same location we have a
      DTD folder.This structure is clear and consistent across all regions
      as well as ICH folder structure specifications.EMEA should
      consider removing the additional util folder from eu folder under
      m1. All necessary files (DTD and style sheet) should be placed in
      their respective folders under one UTIL folder.Also, note that the
      relative path in the XML file should be updated for both DTD and
      style sheet. See Page 30 onwards.Correct path is:../../util/dtd/eu-
      regional.dtd../../util/style/eu-regional.xsl.
      Suggestion: Keep one global (for both ICH and Regional) Util
      folder under submission (sequence) folder. Util dtd - dtd files for
      ICH and regional style – stylesheet for ICH and Regional
In December 2005, a CR was requested to include PIM into the
EU Module 1. This CR requested the following actions:
- Creation of element “m1-3-1-pim” to link to the PIM XML file-
Identify the “util” folder of the EU Module 1 as the appropriate
location for PIM utilities (DTD and style-sheets)
- Amend file formats supported by the EU Module 1 to add XML as
well as the image formats (JPEG, GIF, PNG, TIF, SVG, MathML)
Today, PIM systems are under elaboration and practical
experience provided some feedback about the way PIM has been
integrated into the EU Module 1.
Following the feedback received, we believe that there is a simpler
way to include PIM in EU Module1.
It is more appropriate to include PIM into the EU Module 1 as a
single archive file than directly refer to the XML file. Therefore, it is
proposed to:
- Add ZIP format and TGZ format as valid file formats
- Remove the need to merge “util” folders for PIM and EU Module
1, as the PIM util folder will be stored within the ZIP / TGZ file
- Folder “131-pim-xxxx-ar” is no longer needed because PIM will
be reduced to a single file. The name of that file will be
“131-pim-xxxx-ar.zip ” or “131-pim-xxxx-ar.tgz ” depending on the
format used
Further information included in the original change request.



The link from EU Module 1 to PIM is defined in v1.1 by using the
leaf entity as defined by ICH in the context of eCTD. The leaf entity
is defined by:
- Leaf elements
- Node extension elements (which may contain other leaf and/or
node extension elements)

In the context of a PIM submission, only one PIM file needs to be
attached to the EU Module 1. Also, no concept of node extension
is needed.
Therefore, the EU M1 Specification and DTD need to be updated
to define element “m1-3-1-pim ” so that it can contain only 1 leaf
element

Recommended Solution:

Update Specifications and DTD to define element “m1-3-1-pim”
containing a single leaf element
When providing PIM and/or the XML Electronic application form,
the EU Module 1 eCTD version 1.1 specification indicates that the
corresponding DTDs and stylesheets should be located in the
m1\eu\util directory. Should the DTDs and stylesheets also be
referenced by <leaf> elements within the eu-regional.xml file, or is
this unnecessary as simply serve to support the XML content of
PIM and/or the application form?
Version 1.1 of the EU Module 1 DTD included country and
language codes for the planned accession of Romania and
Bulgaria. Version 1.2 of the DTD included several changes,
including the removal of these country and language codes. Given
the planned accession date of 1st Jan 2007, we believe that these
codes should be in place now to allow use of the eCTD
specification for submissions beginning on January 1st 2007.

Reinstate the country codes into the DTD. Issue an updated
specification document (or alternate form of guidance) stating that
these codes are not to be used in any submission before the
formal accession date of these two countries to the EU. On the
accession date, issue a revision to the specification (or other
guidance note) allowing the use of the country and language codes.


The European Commission website URL is incorrect

The Commission website is referenced on pages 2, 4 and 7 of
Version 1.2 of the specification. The website URL is incorrect. It
should be
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev2.ht
m

The example filenames given for two documents in the
specification are incorrect as they include invalid characters (full
stops). On page 26 of the specification, in the list of the
Directory/File Structure for Module 1, the entries for items 67 and
69 on the list are invalid.

In row 67, the file path and filename is proposed as m1/eu/18-
pharmacovigilance/ 181-phvig-system/phvigsystem.VAR.EXT but it
should include a hyphen rather than a full stop before the VAR
variable, e.g. m1/eu/18-pharmacovigilance/ 181-phvig-
system/phvigsystem-VAR.EXT

Likewise, on row 69 the proposed file path and filename is
m1/eu/18-pharmacovigilance/ 182-riskmgt-
system/riskmgtsystem.VAR.EXT but it should include a hyphen
rather than a full stop before the VAR variable, e.g. m1/eu/18-
pharmacovigilance/ 182-riskmgt-system/riskmgtsystem-VAR.EXT
plemented in EU M1 v1.2.1
                          Comments                             Status              Action

       In fact, the acceptance of 'Other file formats in Implemented in EU         Dec 05:
       accordance with the PIM DES' should be            M1 v1.2.1                 Implemented in
       detailed, as this standard includes more than                               eCTD Spec v1.1 -
       XML (additional documents that can be attached                              accepted file
       with the XML)                                                               formats amended.
       Furthermore the specification has been updated                              Oct 06: Updated in
       to recognise that PIM files are submitted in                                eCTD Spec v1.2.1 -
       archive format as ZIP or TGZ files that contain                              accepted file
       XML and other file formats.                                                 formats amended

       Retain separate util folder for components that         Implemented in EU   Oct 06:
       can be submitted outside eCTD e.g. e-AF and             M1 v1.2.1           Implemented in
       PIM. For those regional components that are                                 eCTD Spec v1.2.1,
       always submitted as part of eCTD, use global                                cell 72, p.28
       util folder to obviate need for regional util folder.
       More testing required of PIM container
Recommended solution                              Implemented in EU   Oct 06:
- Add TGZ as allowed file format (this format is  M1 v1.2.1           Implemented in
preferred as it is more open than the ZIP format)                     eCTD Spec v1.2.1
- Add ZIP as allowed file format
- Add name specification “131-pim-xxxx-
ar.zip/tgz ” for the PIM file
- Keep Element “m1-3-1-pim”
- Remove description the use of EU M1 “util”
folder for PIM
- Remove definition of folder “131-pim-xxxx-ar ”

Refer to PIM DES specifications for
compression protocols




                                                Implemented in EU     Oct 06:
                                                M1 v1.2.1             Implemented in
                                                                      eCTD Spec v1.2.1




They do not have to referece.                   Implemented in EU     Implemented in EU
Check guidance is clear                         M1 v1.2.1             Module 1 eCTD
                                                                      v1.2.1
EU M1 is 1st priority – Lang/country codes for   Implemented in EU   Implemented in EU
RO BU in DTD, specifications and style-sheet.    M1 v1.2.1           Module 1 eCTD
Assessment of required changes to align same                         v1.2.1
requirement in eAF-New eAF-Var. EMEA
Regulatory Affairs to agree to this CR.




                                                 Implemented in EU   Implemented in EU
                                                 M1 v1.2.1           Module 1 eCTD
                                                                     v1.2.1




                                                 Implemented in EU   Implemented in EU
                                                 M1 v1.2.1           Module 1 eCTD
                                                                     v1.2.1
                                           EU eCTD Specification Change Req
 #          Requestor             Specification
                                  Component
A001                          eCTD EU Module 1
                              Specification




A004                          eCTD EU Module 1
                              Specification




A010   The question was        eCTD EU Module 1
       generated by ICH change Specification
       request 00560




A011   The question was        eCTD EU Module 1
       generated by ICH change Specification
       request 00710
 20060524-01     Ron de Boer




CR-20061221-01   Kevin Wing, J&JPRD   eCTD EU Module 1
                                      specification v1.2.1,
                                      page 7




CR-20070118-01   Harv Martens, ING    eCTD EU Module 1
                 America              specification v1.2.1,
                                      examples




CR-20070122-01   Harv Martens, ING    eCTD EU Module 1
                 America              specification v1.2.1,
                                      examples


CR-20070309-01   Kevin Wing, J&JPRD   eCTD EU Module 1
                                      specification v1.2.1
QA-20070627-01   Alastair Nixon, GSK




CR-20070627-01   Alastair Nixon, GSK    eCTD EU Module 1
                                        specification v1.2.1

CR-20070628-01   Thierry Le Ridant,     eCTD EU M1 stylesheet
                 Ethypharm


QA-20070628-02   Thierry Le Ridant,     eCTD EU Module 1
                 Ethypharm              specification v1.2.1




CR-20070628-01   Thierry Le Ridant,     EU Module 1 stylesheet
                 Ethypharm


QA-20070906-01   Hans van Bruggen,      eCTD EU Module 1
                 eCTDConsultancy B.V.   specification v1.2.1
CR-20070906-01   Reinko Abels, Qdossier    eCTD EU Module 1
                 B.V.                      specification v1.2.1




CR-20070926-01   Juan Rueda Montes,        eCTD EU Module 1
                 EMEA                      specification v1.2.1



CR-20070927-01   Ulrika Lantz, AstraZeneca eCTD EU Module 1
                                           specification v1.2.1 and
                                           Guidance on Type 1A
                                           and 1B variations




CR-20071002-01   Juan Rueda Montes,        eCTD EU Module 1
                 EMEA                      specification v1.2.1




CR-20071003-01   Alastair Nixon, GSK       eCTD EU Module 1
                                           specification v1.2.1
CR-20080129-03   Geoff Williams, Roche   eCTD Specification
                                         v1.2.1




 CR-20080218     Andrew Marr, GSK




 CR-20080303     Claire Holmes, EMEA     EU M1 Specification
                                         v1.2.1
EU eCTD Specification Change Requests Implemented in EU M1 v1.3
                               Description

      What is the EU's position on the use of XML for the content of
      the submission instead of PDF and/or RTF?




      What is EU's position on the use of e-signatures in the eCTD?




      Clarification should be provided by all ICH regions as to whether
      node extensions can be used in Modules 2-5
      The ICH spec allows node extensions to be used in Modules 2-5
      and their use in Module 1 is a regional matter. FDA states that
      node extensions are not supported in any part of the submission
      and this therefore invalidates the ICH spec. Experience on
      production of submissions for Europe demonstrates that node
      extensions are required to deliver a navigable structure for
      Modules 4 and 5. At present this means that eCTDs are not re-
      usable across regions and thus will create significant amounts of
      rework for industry. FDA should accept node extensions in
      Modules 2-5.




      Are applicant provided style sheets allowed?
If I submit sequence number 0001. What will be the operation
attribute for the eu-regional.xml in the index.xml?
This can not be replace, because the eu-regional.xml only
contains the updated parts and a replace operation will make all
previously submitted documents obsolete. It is also not new,
because the eu-regional.xml has been submitted before. Should
it perhaps be append?
EU Module 1 Specification v1.2.1 (and predecessors) requests
that the variable component of filenames should be a
“meaningful concatenation of words without separation and
should be kept as brief and descriptive as possible” but also
specifies that hyphens (“-“) should not be used within these
variable components. The change request applied for is to allow
the use of hyphens within the variable component of filenames in
the EU Module 1.
Examples 2 and 3 of the EU Module 1, in the context of v1.2.1,
are incorrect regarding the Specifications.
EU M1 Specifications require PI documents (section 1.3.1) to be
named as follows:
CC/LL/CC-SPCDOC-VAR.EXT
For instance, a French SPC in Belgium should be named, e.g.:
be/fr/be-spc.doc
Examples 2 and 3 name such file with the prefix set to the
language instead of the country: be/fr/fr-spc.doc
Examples need to be updated so that the name of the PI
documents is inline with the EU M1 Specifications.

Examples 2 to 4 contain a util folder within the m1/eu folder. This
folder can exist to hold EU-specific files (DTDs and/or style-
sheets) but in the provided examples, this folder contains the EU
Module 1 DTD files. This is incorrect and can be misleading

Page 39 of EU Module 1 Specification v1.2.1 suggests that the
envelope element of MRP or DCP submissions could be
assigned a country attribute value "common" when the same
sequence is being submitted to multiple countries. The change
request applied for is to change the example to illustrate the use
of multiple repeated country-specific envelopes, instead of a
single envelope labeled “common”.
One principle of the eCTD is that content that is not required for
the dossier is not provided, and there is no need for the applicant
to provide „not applicable‟ pages. However, we have
experienced occasions where we receive questions after EMEA
content validation with respect to sections that are missing in the
eCTD, but where no justification has been provided.
Is it necessary to include statements in the CTD/eCTD justifying
the absence of data? If so, where should these statements be
placed in the CTD structure?
Further information included in the original change request

Error in Appendix 2, suggesting that applicant uses the 10-cover
section for response to questions

Data from the envelope is displayed in blue but they are not
hyperlinks. The use of blue text should be limited to hyperlinks


Is it possible to have a list of value for the <agency-name> in
order to standardised the value of this element.




Data from the envelope is displayed in blue but they are not
hyperlinks. The use of blue text should be limited to hyperlinks


Could the TIGes clarify what <Submission> “type” attribute value
should be selected for the following types of submission:
1. Annual Reassessment
2. Duplex registration
3. Line Extension
The current EU Module 1 specification does not specify that
content files in the ICH section can be pointed to by eCTD leaf
elements in the eu-regional.xml file




Update Specifications re list of procedure types




Many post-approval submission types require a copy of an
already approved specification to be submitted. The basis for
eCTD is to submit documents only once, but to be able to fulfil
the European variation guidelines all required documents would
need to be submitted. This change request gives a suggestion
on how this could be handled in eCTD.
Further information included in the original change request.




Should eCTD Module 1 section "additional data" be empty for
EMEA centralised procedures?




Supporting data for variations that is not provided in m3 is
currently either provided with the cover letter (p13 of EU M1
Specification v121), or as an annex to the form (p14). It is
proposed that all supporting data is provided in the same
location, as an annex to the form. In addition, it is proposed that
ICH eCTD Q&A 46 states “all regions have agreed to accept
PDF 1.4. Please consult regional guidance to submit other
versions of PDF.”. Clarification is required about the
acceptability of versions of PDF other than PDF 1.4 in the EU
region.

It is noted that the planned EU eCTD Validation Criteria will
include a statement that all files should be PDF 1.4.

However, it is also noted that some specific EU NCAs require the
use of Acrobat Forms and other documents created in later
versions of PDF and that do not function as needed if created in
a lower version of PDF. Specific attention is drawn to the MHRA
Application Forms that require Acrobat 7.1 (PDF 1.6) and the
EMEA Paediatric Implementation Plan Application Forms that
require Acrobat 8 (PDF 1.7).

Proposal: Adoption of the following statement in the EU Module 1
Specification document.

PDF files submitted as part of an eCTD must be at least version
PDF 1.4. Earlier versions of PDF must be converted to at least
PDF 1.4. Files created with later versions of PDF may be
submitted as part of a European eCTD.



The Best Practice for eCTD in MRP/DCP (draft v0.4) includes as
requirement to provide a table as a file under 1.0 Cover Letter
that keeps track of the sequences, when and when they have
been submitted. This will allow each NCA to know that any
„missing‟ sequences are not relevant to them and hence have
not been submitted. The example tables in the guidance have
been developed in Word and would be expected to be submitted
as a PDF. However, when an earlier version of the guidance
was provided to vendors for comment, several made a request
that this table is able to be supplied as an xml file as this would
allow it to be generated automatically by the building tools.
Production of a word-processed file would be inefficient.

The proposed new EU M1 CTD Guidance from NtA includes a
new section 1.10 Information relating to Paediatrics. The eCTD
specification should be updated in line with the new CTD
structure.
sts Implemented in EU M1 v1.3
                         Comments                          Status              Action

       Change request added retrospectively to allow       Implemented in EU   Implement in v1.3:
       tracking of the Q&A process                         M1 v1.3             Answered as Question #1.
                                                                               Clarify in Appendix 2 row 6
                                                                               (comments section)



       Change request added retrospectively to allow       Implemented in EU   Implement in v1.3:
       tracking of the Q&A process                         M1 v1.3             Answered as QAA #4. Include
                                                                               a new section alongside
                                                                               'acceptable formats' p.6 stating
                                                                               that reference should be made
                                                                               to national guidance on the use
                                                                               of e-signatures.


       November 2004: The use of node extensions          Implemented in EU    Implement in v1.3:
       should be discussed with FDA on a case by          M1 v1.3              Answered as Q&A #10. Include
       case basis. Other regions are able to accept                            on p.7 an additional section
       appropriate use of node extensions in                                   with agreed text
       compliance with the eCTD specification (i.e. their
       use is discouraged unless there is no other
       feasible means to submit the information).

       May 2005: Referred to EU and MHLW regional
       guidance for specific instances where it can be
       used.

       June 2005: Proposal to come from EFPIA as to
       how node extensions may be accepted in the
       EU. Clarification: FDA strongly discourages
       node extensions. ACTION: EFPIA to circulate
       the proposal to TIGes-J.

       May 2005 - referred to EU and MHLW for              Implemented in EU   Implement in v1.3:
       regional guidance                                   M1 v1.3             Answered as Question 11.
                                                                               Put a comment in appendix
       June 2005: Applicant stylesheets are accepted                           2,row 72.
       in the EU. However, there are improvements to
       be documented and made to the EU stylesheet
       to ensure that its features meet requirements. If
       necessary changes are made, the use of
       company stylesheets should be strongly
       discouraged.
                                                Implemented in EU   Implement in v1.3:
                                                M1 v1.3             Include a clarification in the
                                                                    spec in Appendix row 2 -
                                                                    operation attribute should be
                                                                    'new'. Investigate other
                                                                    locations where an update
                                                                    could be provided.
Sep-07 Proposed for Q&A                         Implemented in EU   Implement in v1.3:
                                                M1 v1.3             Answered as Q&A #16.
                                                                    Change p.7 of the specification
                                                                    'file naming convention'




Mar-07 Accepted to update example files         Implemented in EU   Implement in v1.3:
                                                M1 v1.3             Change as specified




Mar-07 Examples to be corrected, and to         Implemented in EU   Implement in v1.3:
include index.xml and MD5 checksum to reflect   M1 v1.3             Change the 3 examples in all
valid eCTD submissions.                                             the locations as detailed in the
                                                                    change request itself

Sep-07 “Common” should not be an allowable      Implemented in EU   Implement in v1.3:
value for the envelope.                         M1 v1.3             p.6 section 'Envelope' -propose
Change wording to specify the use of multiple                       text for inclusion here. Also
country-specific elements.                                          change example text which
Write a Q&A to clarify until new version is                         illustrates this on p.39
produced                                                            See Q&A #17

                                                                    20080220: See CR-20080129-
                                                                    02
Nov-07 Q&A wording proposed                   Implemented in EU   Implement in v1.3:
                                              M1 v1.3             Answered asQ&A #18.
                                                                  Change text on p.6 to include
                                                                  text from Q&A 18. Add a
                                                                  statement to indicate that
                                                                  further information national
                                                                  guidance should be referred to.




Sep-07 Accepted for next release of           Implemented in EU   Implement in v1.3:
specification                                 M1 v1.3             Remove reference in row 5,
                                                                  appendix 2, p.13
Sep-07 Analysis undertaken of all EU          Implemented in EU
stylesheets shows inconsistency. Change       M1 v1.3
request accepted and will be implemented in
next updates of each stylesheet
Nov-07 EMEA has referred to EUTCT group to    Implemented in EU   Implement in v1.3 if values list
define list                                   M1 v1.3             exists:

                                                                  20080220: List to be
                                                                  implemented in EUTCT - to
                                                                  come from ECD


Sep-07 Analysis undertaken of all EU          Implemented in EU   Implement in v1.3:
stylesheets shows inconsistency. Change       M1 v1.3             Stylesheet to be updated to
request accepted and will be implemented in                       include all black text.
next updates of each stylesheet
Nov-07 Review required across other           Implemented in EU   Implement in v1.3:
specifications. See also CR-20070926-01       M1 v1.3             Propose revised list. See CR-
                                                                  20070926-0 - ensure these
                                                                  values are in the revised list.
                                                                  Also include community
                                                                  referrals.
Nov-07 Accepted with proposed change to           Implemented in EU   Implement in v1.3:
wording to page 6 of the specification.           M1 v1.3             Include a short additional
See also CR-20070927-01                                               section on p.6 under 'General
                                                                      Architecture'. Wording to clarify
                                                                      that content filesin the ICH
                                                                      section can be pointed to from
                                                                      regional leaf elements (see CR-
                                                                      20070927-01)
                                                                      See Q&A #21




Nov-07 Review required across other               Implemented in EU   Implement in v1.3:
specifications. See also QA-20070906-01           M1 v1.3             List should be finalised:
                                                                      Propose final list for agreement
                                                                      by NtA Interlinking/TIGes

Nov-07 The eCTD specification already defines     Implemented in EU   Implement in v1.3:
how to reference content from more than one       M1 v1.3             Include a short additional
leaf location. Some clarity might be added to                         section on p.6 under 'General
specification.                                                        Architecture'. Wording to clarify
See also CR 20070906-01                                               that content filesin the ICH
                                                                      section can be pointed to from
                                                                      regional leaf elements (see CR-
                                                                      20070906-01)
                                                                      See Q&A #21




Feb 08: Specify in EU M1 v1.3 that this section   Implemented in EU   Answered as Question 20
can be used for CP in a transition period for     M1 v1.3             Refer to CTD Guidance #4 on
submitting documents as part of a new M1                              use of the additional data
structure before the latest DTD version is                            section (i.e. it should not be
implemented (e.g. paediatrics data).                                  used for CP) - amend therefore
                                                                      line 68 of the table in appendix
                                                                      2



Nov-07 An EU CTD Q&A (4c) already exists          Implemented in EU   Implemented Appendix 2 row
about the placement of additional documents in    M1 v1.3             72.
Variations. Accepted to update EU M1 eCTD
specification in line with CTD Q&A response.
Feb 08: New proposal with simpler wording to      Implemented in EU   Implemented on Page 5
come from EFPIA, clarifying further the use of    M1 v1.3
PDF versions.
N.B. EU Validation Criteria specify v1.4 (but
warning only).

All PDF files included in the eCTD should be
v1.4 except where there is an agency specific
requirement for a later version eg. for an
application form.




To be included in eCTD v1.3 2008                  Implemented in EU   Implemented in Appendix 2
                                                  M1 v1.3             Line 4
Format and layout of the table to be defined by
eCTD Interlinking Group.




                                                  Implemented in EU   Included in DTD and througout
                                                  M1 v1.3             the document
                                                                                                                                            EU eCTD Specification Change Requests                                                                                                                                                                                                                                                           ACTION JUNE
              #         Requestor            Specification                                                                                                            Comments                                    Status                         Action                      Group Where                                  Notes                                        ACTION JUNE                               DTD / Style-                       Specifications                              Comments
                                              Component                                                                                                                                                                                                                      Action is Sitting                                                                                                                  sheet Change                           Change
             A004    generated by EU                                 What is EU's position on the use of e-signatures in the eCTD?                 A crucial part of pure electronic communications           Approval date:      Text Included in EU M1 v1.4
                     Change Request                                                                                                                between the pharmaceutical industry and                      1.3.2007
                     A004                                            This question was generated by EU Change Request A004                         regulatory agencies and authentication of
                                                                                                                                                   electronic submissions or documents contained
                                                                                                                                                   in electronic submissions will be the use of digital
                                                                                                                                                   signatures. Currently the EU is developing a
                                                                                                                                                   (long-term) strategy to implement digital
                                                                                                                                                   signatures. As yet, digital signatures cannot be
                                                                                                                                                   used or supported in electronic submissions in
                                                                                                                                                   the EU.

             A009    generated by EU                                 M3 requires each substance-manufacturer and drug product to be                The ICH CTD guidance recommends that the                   Approval date:      Text Included in EU M1 v1.4
                     Change Request                                  added in a separate subfolder. How should a product be added to the           applicant repeat the complete Module 3.2.S for               1.2.2008
                     A009                                            structure if it has multiple substances?                                      each drug substance that makes up the drug
                                                                                                                                                   product. The ICH eCTD specification allows the
                                                                     This question was generated by EU Change Request A009                         repeat of the Module 3.2.S within the XML
                                                                                                                                                   backbone. Therefore, the applicant should
                                                                                                                                                   create the eCTD in this way.
             A011    generated by ICH                                In the eCTD for the EU, are applicant provided style sheets allowed?          Little advantage is to be gained by the use of             Approval date:      Text Included in EU M1 v1.4
                     change request                                                                                                                custom stylesheets. The XML instance can only                1.3.2007
                     00710 and the                                   The question was generated by ICH change request 00710 and the                point to one stylesheet and the inclusion of a
                     response to ICH                                 response to ICH eCTD Question 30. This is recorded as EU Change               reference to a stylesheet that is not the regional
                     eCTD Question                                   Request A011.                                                                 one would prevent the agency using the official
                     30. This is                                                                                                                   EU stylesheet. It is therefore recommended not
                     recorded as EU                                                                                                                to submit customised stylesheets.
                     Change Request
                     A011.
             A014    generated by ICH                                What is the EU regional guidance relating to the ability to cross-            In the EU it is possible to refer to a file located in     Approval date:      Text Included in EU M1 v1.4              N/A                       Include text from Q&A 14 in the spec. v1.4           Update spec p.7 according to Q&A #14.              Extended Example 1         Added statement and example under
                     change request                                  reference from one sequence to files in another sequence?                     the same sequence or any previous sequence of                1.3.2007                                                                             indicating that references can be made to files                                                         with reference to a file   "General Architecture of Module 1", page
                     01080 and the                                                                                                                 the same eCTD. It is not possible to refer to                                                                                                     located in another sequence.                         Update spec. further with information on how       in Module 2                7. Example refers to a file in another
                     response to ICH                                                                                                               other eCTDs.                                                                                                                                                                                           sequences are stored as mentioned in 'Notes'                                  sequence and another module:
                     eCTD Question                                                                                                                                                                                                                                                                   LD: Need to express how sequences are                column.
                     37. This is                                                                                                                                                                                                                                                                     assumed to be stored (e.g. 0000 next to 0001)                                                                                      "Files can be referred to across
                     recorded as EU                                                                                                                                                                                                                                                                  so as to allow relative reference (e.g. ../../0000                                                                                 modules (e.g. from Module 1 to Module
                     Change Request                                                                                                                                                                                                                                                                                                                                                                                                     2) or across sequences within the same
                     A014.                                                                                                                                                                                                                                                                           Suggest inclusion at the end of 'General                                                                                           eCTD application; note however that it
                                                                                                                                                                                                                                                                                                     Architecture of Module 1 (Page 7)                                                                                                  is not possible to refer to files in other
                                                                                                                                                                                                                                                                                                                                                                                                                                        eCTD applications. When referring to
                                                                                                                                                                                                                                                                                                                                                                                                                                        files across modules or across
                                                                                                                                                                                                                                                                                                                                                                                                                                        sequences, the reference must always
                                                                                                                                                                                                                                                                                                                                                                                                                                        be relative, starting from the location of
                                                                                                                                                                                                                                                                                                                                                                                                                                        the XML file. For instance, a reference
                                                                                                                                                                                                                                                                                                                                                                                                                                        from within Module 1 of Sequence 0003
                                                                                                                                                                                                                                                                                                                                                                                                                                        (e.g. 0003/m1/eu/ eu-regional.xml) to a
                                                                                                                                                                                                                                                                                                                                                                                                                                        file located in Module 2 of Sequence
                                                                                                                                                                                                                                                                                                                                                                                                                                        0000 (e.g. file “introduction.pdf” in folder
                                                                                                                                                                                                                                                                                                                                                                                                                                        0000/m2/22-intro), would be encoded in
                                                                                                                                                                                                                                                                                                                                                                                                                                        the EU Module 1 as “../../../0000/m2/22-
                                                                                                                                                                                                                                                                                                                                                                                                                                        intro/introduction.pdf”. ".




             0014    EFPIA (A. P. Marr)   eCTD EU Module 1           The newly agreed ICH Q&A #38 on referring to files submitted in        ICH Answer :At this stage of the implementation                 Answered in Q&A                                                N/A                       Include text from Q&A 14 in the spec. v1.4           Update spec p. 7 as above with text from Q&A                                  See previous change for details.
                                          Specification              previous sequences indicates that we should refer to regional guidance of the eCTD, the four Operation Attributes (new,                                                                                                         indicating that references can be made to files      #14, so state that references can be made to
                                                                     with respect to allowance of cross-referral. This guidance needs to be append, replace and delete) will remain and not                                       Referred to ICH for next major version                             located in another sequence.                         files located in another sequence.
                                                                     established.                                                           be added to. With the existing specification it is                                    of the eCTD.
                                                                                                                                            technically possible to determine that a file is not                                                                                                     Suggest inclusion at the end of 'General
                                                                                                                                            in the current eCTD.                                                                                                                                     Architecture of Module 1 (Page 7)

                                                                                                                                                                                                                                                                                                     See A014.

             CR-    generated by EU                                  The EU eCTD Specification v1.2.1 states that the variable component           No it is not acceptable to use a hyphen. In cases          Approval date:      Text Included in EU M1 v1.4
          20061221- Change Request                                   of filenames should be a “meaningful concatenation of words without           where differentiation is needed it is suggested              1.3.2008
              01    CR-20061221-01                                   separation and should be kept as brief and descriptive as possible” but       that the word 'point' is used in the filename eg.
                                                                     also specifies that hyphens (“-“) should not be used within these             1point5mg
                                                                     variable components. There are occassions where there needs to be
                                                                     differentiation between documents, for example, strength (1.5mg or
                                                                     15mg). Is it acceptable that under such circumstances to use a
                                                                     hyphen to differentiate between documents.

                                                                     This question was generated by EU Change Request CR-20061221-01


             CR-    Ashley Birch,         ICH eCTD Q&A 40            ICH eCTD Question Number 40 asks whether it is acceptable to                                                                           Rejected              Discussed at ICH M2, see ICH tracking TIGes                        Clarify in EU M1 v1.4 the use of PDF v1.4, if        Update specification to clarify the use of PDF                                No action taken as the requirement
          20070215- AstraZeneca                                      submit PDF V1.4 files across all regions. Although the answer given is                                                                                       sheet for details of outcome.                                      any decision has been reached at ICH level.          v1.4 according to latest ICH decision                                         remains at PDF V1.4 (with exceptions
              01                                                     in the affirmative, it actually goes much further than mere „acceptability‟                                                                                                                                                                                                          (information can be gained from Geoff from                                    for HA application forms that use a
                                                                     by appearing to make V1.4 mandatory for eCTDs.                                                                                                                                                                                                                                       Yokahama ICH meeting)                                                         higher version). The existing text on
                                                                                                                                                                                                                                                                                                                                                                                                                                        Page 5 reflects this already: "Note that
                                                                                                                                                                                                                                                                                                                                                                                                                                        all PDF files included in an eCTD
                                                                                                                                                                                                                                                                                                                                                                                                                                        (irrespective of the module) should be
                                                                                                                                                                                                                                                                                                                                                                                                                                        v1.4, except where there is an agency-
                                                                                                                                                                                                                                                                                                                                                                                                                                        specific requirement for a later version
                                                                                                                                                                                                                                                                                                                                                                                                                                        (e.g. for an application form) ".

             CR-    generated by EU                                  The EU eCTD Specification v1.2.1 states that the envelope element of          The envelope should be repeated for each                   Approval date:      Text Included in EU M1 v1.4
          20070309- Change Request                                   MRP or DCP submissions could be assigned a country attribute value            member state and 'common' should not be used.                1.2.2008
              01    CR-20070309-01                                   "common" when the same sequence is being submitted to multiple                 The specification will be updated at the next
                                                                     countries. Isn't it more appropriate to utilise a separate envelope for       version to correct this.
                                                                     each Member State?

                                                                     This question was generated by EU Change Request CR-20070309-01

             QA-    generated by EU                                  Is it necessary to include statements in the CTD/eCTD justifying the For new applications, detailed statements                           Approval date:      Text Included in EU M1 v1.4
          20070627- Change Request                                   absence of data? If so, where should these statements be placed in   justifying absence of data or specific CTD                            1.3.2008
             01     QA-20070627-01                                   the CTD structure?                                                   sections should be provided in the relevant
                                                                                                                                          Quality overall summary and/or non-
                                                                     This question was generated by EU Change Request QA-20070627-01 clinical/clinical overviews (Module 2.3, 2.4, 2.5).
                                                                                                                                          Note that placeholder documents highlighting 'no
                                                                                                                                          relevant content' should not be placed in the
                                                                                                                                          eCTD structure, as these would create a
                                                                                                                                          document lifecycle for non-existent documents
                                                                                                                                          and unnecessary complication and maintenance
                                                                                                                                          of the eCTD.
                    Phyllis Thomas,
        QA-20070816-01                                               In Europe (and with the current ICH M2 eCTD specification), does the Sep-07 Question to be referred to ICH M2 Q&A.                       Approval date:                                               TIGes                     Possibly update the text of EU M1 v1.4 to            Update spec to indicate that metadata cannot       None                       New subsection introduced on 'Updating         In eCTD, metadata concern
                    AstraZeneca                                      applicant need to update attributes in the eCTD backbone during the  An EU Q&A to be prepared in the interim period                        1.3.2008          Refer to ICH Q&A                                                   clarify that metadata cannot be amended              be amended during lifecycle. Include text from                                backbone attributes' (Page 7). Following       manufacturer, substance,
                                                                     life an application, for example, if the manufacturers name changes, Answer: Reference is made to ICH Q&A #3. It is                                          Text Included in EU M1 v1.4                                        during the lifecycle of an application.              Q&A #19. Include in the Q&A information that                                  text included:                                 product… and they can
                                                                     the proposed name of the dosage form is not accepted or an excipient not possible to update the attributes nor is it                                                                                                                                                                 the meta-data in the envelope CAN be updated                                  "It is not possible to update XML              change throughout the
                                                                     is granted a pharmacoepial name?                                     necessary to attempt workarounds such as                                                                                                                   LD: Need to further define the set of metadata       however (we need this for a change i                                          backbone attributes such as                    lifecycle. In EUM1, metadata
                                                                     Further detail included in original question.                        deleting existing documents and resubmitting                                                                                                               that needs to remain throughout the life cycle       submission type during the lifecycle under the                                „manufacturer‟ during the eCTD                 concern country, language
                                                                                                                                          with new attributes. The recommendation is to                                                                                                              of the product                                       new variation regulation) - the restriction only                              lifecycle, nor is it necessary to attempt      and type of PI document,
                                                                                                                                          retain the obsolete entry and to rely on the                                                                                                                                                                    applies to structural metadata.                                               workarounds such as deleting existing          which should be very stable,
                                                                                                                                          document content to explain the current details.                                                                                                           AB: Also include in eCTD guidance                                                                                                  documents and resubmitting them with           unless typo. Also, eCTD can
                                                                                                                                                                                                                                                                                                                                                          Further update spec to define the metadata                                    new attributes. The recommendation is          have a lot of info attached to a
                                                                                                                                                                                                                                                                                                                                                          that should remain throughout the lifecycle.                                  to retain the obsolete entry and to rely       metadata (costly to replace)
                                                                                                                                                                                                                                                                                                                                                                                                                                        on the document content to explain the         while EUM1 has few
                                                                                                                                                                                                                                                                                                                                                                                                                                        current details. The sole exception to         information (less costly to
                                                                                                                                                                                                                                                                                                                                                                                                                                        this rule is the EU envelope submission        replace). Shouldn't we support
                                                                                                                                                                                                                                                                                                                                                                                                                                        type attribute, which can be updated to        the possibilty to correct or
                                                                                                                                                                                                                                                                                                                                                                                                                                        support a change in submission type            replace these "metadata" in
                                                                                                                                                                                                                                                                                                                                                                                                                                        (under the new variation regulation). "        EUM1?

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       Note added page 7
                     generated by
CR-20070906-01 & CR-20070927-01 EU                                   Can content files that are included in the index.xml (ICH Modules 2-5)        Yes. For appendices to the application form                Approval date:      Text Included in EU M1 v1.4
                     Change Requests                                 also be referred to in the eu-regional.xml?                                   which may also be located in module 3, it is                 1.3.2008
                     CR-20070906-01                                  This question was generated by EU Change Requests CR-20070906-                recommended to create a leaf in the eu-
                     & CR-20070927-01                                01 & CR-20070927-01                                                           regional.xml that points to the content located in
                                                                                                                                                   module 3 e.g. Flow Chart of the Manufacturing
                                                                                                                                                   Sites, and Ph.Eur Certificate. Other scenarios
                                                                                                                                                   where this approach should be used include type
                                                                                                                                                   Ia and Ib variations, where content is requested
                                                                                                                                                   in module 1 which is available in pre-existing
                                                                                                                                                   locations in module 3, e.g. copy of the approved
                                                                                                                                                   specification.

                     generated by EU
        CR-20071002-01                                               Should eCTD Module 1 section "additional data" be empty for EMEA     Yes. The Notice to Applicants CTD Q&A #4C                           Approval date:      Text Included in EU M1 v1.4
                     Change Request                                  centralised procedures?                                              states that the 'Additional Data" should only be                      1.3.2008
                     CR-20071002-01                                  This question was generated by EU Change Request CR-20071002-01 used for information required for National, MRP
                                                                                                                                          and Decentralised Procedures and is therefore
                                                                                                                                          not applicable for the Centralised Procedure
                                                                                                                                          except during a transition period when an old
                                                                                                                                          version of a DTD is being used to support
                                                                                                                                          inclusion of a newly defined section of Notice to
                                                                                                                                          Applicants ie. paediatric data which will be
                                                                                                                                          included in EU specification Module 1 v1.3 as a
                                                                                                                                          new section 1.10 Information relating to
                                                                                                                                          Paediatrics.
             QA-    Alastair Nixon,                                  In the eCTD, how should an applicant handle multiple variations that Nov-07 Best Practice guide written for review                     Accepted - refer to   Present guidance for consideration by    eCTD Interlinking Group   Ensure this is addressed as part of the              Decided not for EU M1 specification -                                         None                                           Not for inclusion in EU M1
          20071022- GSK                                              occur in parallel and affect the same document?                      and approval                                                      eCTD Interlinking     Interlinking                                                       analysis of the new variation regulation. Will       instead, specific example scenarios to be                                                                                    spec - for guidance instead.
             01                                                                                                                           March-09 : Subgroup to be established to                          Group                                                                                    probably lead to changes to the EU M1                built and to be included in later guidance
                                                                                                                                          address all issues of variation, in the context of                                                                                                         specification (v1.4)                                 accompanying the new variation regulation.
                                                                                                                                          the new Variations Regulations. This CR will be
                                                                                                                                          addressed within this group.                                                                                                                               Priority: High

             CR-    Geoff Williams,       EU M1 stylesheet           The current stylesheet displays the full structure of the Module 1,                                                                    Rejected              None                                     N/A                       No further action required by EU with regard to      Include a note in the spec to describe the EU      None                       Added statement under "Handling of
          20080129- Roche                                            whether the displayed sections have content or not. This is a little                                                                                                                                                            EU M1 v1.4                                           M1 stylesheet approach.                                                       Empty or Missing eCTD Sections", page
              01                                                     confusing as it gives the impression of much more information than is                                                                                                                                                                                                                                                                                              7:
                                                                     really present. In addition, some sections are mutually exclusive and                                                                                                                                                           LD: Include a note in the Spec about the                                                                                           "The EU Module 1 is provided with a
                                                                     others only apply for particular procedure types.                                                                                                                                                                               approach of the style-sheet, i.e. to display all                                                                                   rendering style-sheet that can be used
                                                                     The display of the complete structure is not consistent with the                                                                                                                                                                the entries in the ToC even if there is no                                                                                         to visualise content. Note that the style-
                                                                     behaviour of the ICH stylesheet, which only displays sections that have                                                                                                                                                         content attached to some sections.                                                                                                 sheet has been designed to display the
                                                                     content.                                                                                                                                                                                                                                                                                                                                                           complete table of contents (ie, all the
                                                                     Proposal: Change the stylesheet so that it only displays sections that                                                                                                                                                                                                                                                                                             sections), irrespective of whether files
                                                                     have content.                                                                                                                                                                                                                                                                                                                                                      are actually present in those sections or
                                                                                                                                                                                                                                                                                                                                                                                                                                        not. "

             CR-    Geoff Williams,       EU Module 1 DTD, eu-       A previously submitted CR (20070309-01) proposed the prohibition              Feb 08: New change request to be submitted by            Withdrawn             None                                     TIGes                     Related to CR 20090506 which will be                 Update the spec to clarify the use of 'common'     No deletion of             Definition of 'common' updated          Cf. CR-20090506
          20080129- Roche                 envelope.mod and           against the use of “common” as an acceptable country identifier in the        EFPIA proposing a 'softened' approach where                                                                                                       implemented in EU M1 v1.4 (clarification of the      in line with CR 20090506 from Bil Ali, and the     "common" country           throughout the document in line with
              02                          Specification, v1.2.1      EU Module 1 envelope. This CR seeks to clarify the use, or otherwise,         the country identifier 'common' can be used in                                                                                                    use of 'common').                                    ensuing discussions in the TIGes May.              value                      recent TIGes decision:
                                                                     of the country identifier “ common” for content files in the EU Module 1.     certain circumstances.                                                                                                                                                                                                                                    Cf. row 19 for             "The folder name "common" should only
                                                                                                                                                                                                                                                                                                                                                                                                             clarification of the       be used for documents applicable to all
                                                                     Currently, no clear guidance exists about the correct use of the country May 2009: related to CR-20090506 from Bil Ali of                                                                                                                                                                                                               usage of "common"          EU countries, irrespective of whether
                                                                     identifier “common” when creating an EU Module 1 eCTD, particularly         Shire.                                                                                                                                                                                                                                                      value                      they are receiving the submission or
                                                                     in relation to the application of this country identifier to content files.                                                                                                                                                                                                                                                                                        not."
                                                                     This has led to an inconsistency in usage of the value for the country
                                                                     attribute.

                                                                     A country identifier is used for content included in sections of Module 1
                                                                     that can contain country specific content. The original intent of the
                                                                     “common” country value was to provide some means of identifying
                                                                     content that was used submitted in a section that can contain country
                                                                     specific information but, in this particular submission, is reused by
                                                                     several countries.

                                                                     Propsal:The submitter of this CR proposes completely removing the
                                                                     country identifier “common” from the list of acceptable country identifier
                                                                     values. Specific guidance should be included about to how to manage
                                                                     content that is used in more than one country.
             CR-    Ms Nadine             EU Module 1                As a manufacturer for plasma products, CSL have a centrally                   Refer to eCTD Interlinking Group to write interim        Accepted - refer to   Draft guidance on the use of eCTD for    eCTD Interlinking Group   eCTD PMF Guidance published June 2009. In            Update DTD to include a submission type            Added element "pmf"       Added "pmf" in Appendix 1
           20080415 Schwarz               specification, Appendix    authorised Plasma Master File (PMF). Following the centralised                guidance on which submission type to use.                eCTD Interlinking     PMF.                                                               addition, the inclusion of a submission type         'pmf'.                                             in Envelope DTD
                    CSL Behring AG        1 "Envelope Element        authorisation of the PMF the PMF 2nd Step Procedure must be                   March-09 : Draft guidance is under development           Group                                                                                    'PMF' should be included in the EU M1                                                                   Added mapping
                                          Description", therein      performed. In this 2nd Step Procedure, the PMF certificate must be            by EMEA, taking into account the new                                                                                                              specification v1.4, list of envelope 'submission                                                        between code and
                                          element = submission       submitted for each product in order to make the link between PMF and          regulations, and will be circulated to the                                                                                                        type' values.                                                                                           definition in style-sheet
                                          and attribute = type (p.   the product's marketing authorisation. According to the "Guideline on         Interlinking group for endorsement
                                          10)                        Plasma Master File (PMF) And Vaccine Antigen Master File (VAMF)
                                                                     “Second Step”" this is NOT a variation submission.
                                                                     If this is done for an existing eCTD, there is no adequate submission
                                                                     type defined in the Module 1 Specification to describe this submission.
                                                                     Recommendation: Define an additional valid submission type for a
                                                                     PMF 2nd Step Submission, such as "pmf-2nd-step".
                                                                                                                            EU eCTD Specification Change Requests                                                                                                                                                                                                                                                    ACTION JUNE
    #        Requestor          Specification                                                                                                        Comments                                   Status                         Action                       Group Where                                  Notes                                        ACTION JUNE                             DTD / Style-                  Specifications                           Comments
                                 Component                                                                                                                                                                                                                  Action is Sitting                                                                                                                sheet Change                      Change
  CR-    Kevin Wing,         EU Module 1              The example provided for the application number element description          Refer to eCTD Interlinking Group for discussion       Open                  Complete the survey for MS on          TIGes                         Clarification of the use of the application         Rename 'application number' to 'tracking           Amended examples,      Amended definition and example in          Used DE/UK numbers in Spec
20080514 eCTDConsultancy     Specification v1.2.1     on page 9 of the guidance is in the format of an EMEA Marketing              and drafting of Q&A on what is expected in that                             requirements for application/procedure                               number provided in the envelope will most           number' in the specification. Update spec to       with                   Appendix 1                                 and Examples
                                                      Authorisation Number i.e. EU/1/00/150/001 and not an EMEA                    field. Draft survey for MS on requirements for                              number, and use of this element. Once                                likely be needed in EU M1 v1.4, as well as a        clarify the use of the current 'tracking number'   EMEA/H/C/XXX/X/XX      Amended examples in Appendix 4, with
                                                      Procedure Number such as EMEA/H/C/XXX/X/XX.                                  application/procedure number, and use of this                               results have been gathered, produce a                                change to the provided example in the spec.         field in the envelope, based on the changes        for CP procedure       EMEA/H/C/XXX/X/XX for CP procedure
                                                                                                                                   element.                                                                    new change request as appropriate                                    Exact instructions for clarification/change still   made to the envelope for the new variation         number, and            number, and MS/H/XXXX/XXX/XX/XXX
                                                      The accompanying description that this is the “number assigned to the                                                                                    requesting a change to the way                                       need to be provided by the TIG                      regulation.                                        MS/H/XXXX/XXX/XX/XX for other procedures
                                                      application by the receiving agency” suggests that what is meant here                                                                                    application numbers are captured in                                                                                                                                         X for other procedures
                                                      is the procedure number, and not the marketing authorization number                                                                                      the envelope.
                                                      (which would only be assigned upon approval and would also be
                                                      strength-specific). This is supported by the explanation provided on
                                                      page 14 of the EMEA‟s recently released Q&A on eCTD
                                                      Implementation (7th February 2008).
                                                      Change the example for the application number element from:
                                                      EU/1/00/150/001
                                                      to
                                                      EMEA/H/C/XXX/X/XX.
                                                      And add a clarification to the description that the number required for
                                                      this value is the procedure number.
CR-         Anne Mieke    EU Module 1                 Since this information is mandatory in the cover letter, variation and       Refer to eCTD Interlinking Group for discussion       Open                  Complete the survey for MS on          TIGes                         Clarification of the use of the application         Rename 'application number' to 'tracking           No change regarding   Application number' changed to 'tracking Used DE/UK numbers in Spec
20080514-    Reijnders,   Specification v1.2.1        renewal application form and is useful for retrieving information from       and drafting of Q&A on what is expected in that                             requirements for application/procedure                               number provided in the envelope will most           number' in the specification. Update spec to       authorisation         number'. Description changed to include and Examples
01        eCTDConsultancy                             the eCTD lifecycle it would be beneficial to add the Marketing               field. Draft survey for MS on requirements for                              number, and use of this element. Once                                likely be needed in EU M1 v1.4, as well as a        clarify the use of the current 'tracking number'   numbers, but          examples of the various different agency
                                                      Authorization Numbers to the EU M1 envelope information.                     application/procedure number, and use of this                               results have been gathered, produce a                                change to the provided example in the spec.         field in the envelope, based on the changes        clarification on      numbers.
                                                                                                                                   element.                                                                    new change request as appropriate                                    Exact instructions for clarification/change still   made to the envelope for the new variation         procedure numbers
                                                                                                                                                                                                               requesting a change to the way                                       need to be provided by the TIG                      regulation above
                                                                                                                                                                                                               application numbers are captured in
                                                                                                                                                                                                               the envel                                                            Same as 20080514

   CR-    Kevin Wing,        EU Module 1              The EU Module 1.2.1 specification only includes instructions relating to TIGes 6 March 09 : Progress revised Q&A that         Accepted                   Implement in next version of EU M1         TIGes                     Implement revised text as provided by Kevin         Include new text as provided by Kevin (assess      None                  Amended Appendix 1 according to text
20080514- eCTDConsultancy    Specification v1.2.1     1.3.1 SPC, Labelling and Package Leaflet identifiers and                   incorporates 'refer to regional guidance' for ICH                             specification v1.4.                                                  Wing in EU M1 v1.4                                  first in light of the new variation regulation                           from KW
    02                                                Language/Country Codes in the context of document filenames/folder         Q&A 57 relating to the use of xml:lang                                                                                                                                                                 changes).
                                                      paths. This information is also required as XML metadata and this                                                                                                                                                             Text may need to be amended in light of new
                                                      change request is to update the specification to clarify this requirement. May 2009: Proposal for text received by Kevin                                                                                                      variation regulation.
                                                                                                                                 Wing for inclusion in the next specification
                                                                                                                                 version.
   CR-    Kevin Wing,        EU Module 1              The concept of the Regulatory Activity was introduced within the EU 3      Refer to guidance on use of related sequence,      Accepted - refer to        Following completion of the EU survey,     TIGes                     Related to CR 20080514, and the use of the       If time allows, state in the spec that the                                  Following text now preceeds the first
20080514- eCTDConsultancy    Specification v1.2.1     years ago and has been presented/discussed at conferences,                 which has been improved and is robust with EU      Q&A                        produce Q&A on use of                                                application number. Clarification of the use of related sequence number is used together                                     paragraph of the Related Sequence
    04                                                implemented by some vendors and is included as a term in the               M1 v1.3.                                                                      application/procedure numbers and                                    the application number particularly with regard with the application number to identify                                      example:
                                                      EMEA‟s Q&A Relating to Practical and Technical Aspects eCTD                EMEA Q&A guidance should be amended to                                        include this clarification in EU M1 v1.4                             to the grouping of submissions into reglatory   submissions as belonging to the same                                         "The Related Sequence number is
                                                      Submission (7th February 2008).                                            refer to EU guidance on use of related sequence,                                                                                                   activities should probably be provided in EU M1 regulatory activity.                                                         used, together with the Tracking
                                                                                                                                 but to indicate that application number is used in                                                                                                 v1.4.                                                                                                                        Number, to identify sequences
                                                      The “Example of the use of the Related Sequence” section on page 11 addition. Depend                                                                                                                                                                                                                                                                       belonging to the same „regulatory‟
                                                      of the EU M1 eCTD guidance describes use of the related sequence                                                                                                                                                              Unlikely that this can be implemented due to                                                                                 activity‟. "
                                                      element to groups eCTD sequences into 3 Regulatory Activities (an                                                                                                                                                             time needed to finalise requirements - see CR-
                                                      MAA, a technical variation and a labelling change variation).                                                                                                                                                                 20080514

                                                      In the afore-mentioned EMEA Q&A document, it is the Application
                                                      Number (procedure number) that is described as the “envelope
                                                      element which is used to group together submissions relating to a
                                                      particular regulatory activity”.

                                                      Could the TIGes provide feedback/guidance on whether the Application
                                                      Number or Related Sequence is the element used to group sequences
                                                      together within a Regulatory Activity. If the Related Sequence is not
                                                      used for grouping together Regulatory Activities, could the TIGes
                                                      comment on what value this element is adding to the EU specification?


CR-         Anne Mieke    EU Module 1                 The application number element description on page 9 of the guidance See CR-20080514-04 -guidance to be produced.                  Open                  Complete the survey for MS on          TIGes                         Clarification of the use of the application         Rename 'application number' to 'tracking           No change regarding   Application number' changed to 'tracking Is that enough to answer the
20080514-    Reijnders,   Specification v1.2.1        states that this is the “number assigned to the application by the                                                                                       requirements for application/procedure                               number provided in the envelope will most           number' in the specification. Update spec to       authorisation         number'. Description changed to include question, about the possibility
05        eCTDConsultancy                             receiving agency”. Given the explanation provided on page 14 of the                                                                                      number, and use of this element. Once                                likely be needed in EU M1 v1.4, as well as a        clarify the use of the current 'tracking number'   numbers, but          examples of the various different agency to use several numbers?
                                                      EMEA‟s recently released Q&A on eCTD Implementation (7th February                                                                                        results have been gathered, produce a                                change to the provided example in the spec.         field in the envelope, based on the changes        clarification on      numbers.                                 To assess
                                                      2008) we presume that for Centralised Submissions, the EMEA                                                                                              new change request as appropriate                                    Exact instructions for clarification/change still   made to the envelope for the new variation         procedure numbers                                              Used statements from CH
                                                      procedure number is meant here (see accompanying change request).                                                                                        requesting a change to the way                                       need to be provided by the TIG                      regulation - see CRs 20080514 01 and 02
                                                                                                                                                                                                               application numbers are captured in                                                                                      above.                                             Renamed element
                                                      In DCP, MRP and especially National Procedures already several                                                                                           the envel                                                                                                                                                                   "application" to
                                                      numbers are used to identify a submission. To avoid misunderstanding                                                                                                                                                                                                                                                                 "tracking"
                                                      clear definitions and guidance of what number to use where is needed.                                                                                                                                                                                                                                                                Amended style-sheet
                                                                                                                                                                                                                                                                                                                                                                                           and examples
                                                      For instance in The Netherlands for a MRP submission the MRP                                                                                                                                                                                                                                                                         accordingly
                                                      procedure number and a case number has to be used (and of course
                                                      the MA number).

                                                      Could the TIGes provide feedback/guidance on the definition of the
                                                      Application Number element for MRP, DCP and National Procedures.



  CR-    Remco Munnik,       EU M1 Specification      In the text of page 16, under nr 4 it mentions: 'Note that the tracking      Include the common folder in the examples for         Accepted              Implement in next version of EU M1         TIGes                     Clarify the use of 'common', and include            Update the spec to clarify the use of 'common'     Examples amended      Renamed "tracking.pdf" into "common-
20080806 Sandoz              v1.3                     table required with MPR/DCP submissions should be located within a           MRP on page 37                                                              specification v1.4.                                                  examples of correct use for all procedures in       in line with CR 20090506 from Bil Ali, and the                           tracking.pdf" to follow naming
                                                      'common' directory, with the filename 'tracking.pdf' or 'tracking.xml‟.      Include the tracking table in the example for MRP                                                                                                EU M1 v1.4. Extract all screenshots and             ensuing discussions in the TIGes May.                                    convention,
                                                      However when you look to the examples for MRP and DCP, the                   and DCP on page 45.                                                                                                                              examples from the specification into a              Update the examples p. 37 and 45.                                        Amended MRP and DCP example (p.45)
                                                      tracking table is not included in the folder m1/eu/10-cover/common.          March-09 : Confirmed by Interlinking                                                                                                             separate document (as agreed in TIGes 29th
                                                      Also in the screenshot on page 37, there should be a common folder                                                                                                                                                            May 2009)
                                                      under m1/eu/10-cover, which is missing.


  CR-    Remco Munnik,       EU Module 1              Discrepancy in guidance on where to store additional documentation           The CTD Q&A 4c is correct and should be               Accepted - refer to   Produce Q&A referring to renewal           eCTD Interlinking Group   Clarify in EU M1 v1.4 the placement of              Update the spec according to the notes in the                            Text in Appendix 2 (Row 72) is already
20081023 Sandoz (EGA)        Specification v1.3       for variations that do not have a place in CTD structure. No guidance        observed - Where documents cannot be                  Q&A                   guidance for the placement of                                        additional documents for variations (according      'comments' column.                                                       aligned with this position. However, have
                                                      for renewals is available.                                                   assigned to specific CTD-defined locations then                             documents.                                                           to the specific Q&A that should be written with                                                                              now added additional text to make it
                                                                                                                                   they should be included in 1.2 Application Form.                                                                                                 regard to this).                                                                                                             clear that this approach also applies to
                                                                                                                                   These might include declarations, certificates,                                                                                                                                                                                                                               renewals:
                                                                                                                                   justifications etc. Where possible, they should be                                                                                               Could possibly go in guidance instead of EU                                                                                  "Supporting data for variations should
                                                                                                                                   organised according to the Annexes for the                                                                                                       M1 specification?                                                                                                            be not be placed in this section;
                                                                                                                                   Application Form for new products (Annexes 1 to                                                                                                                                                                                                                               wherever possible they should be
                                                                                                                                   22). Where documents cannot be assigned to                                                                                                                                                                                                                                    placed in the relevant CTD section,
                                                                                                                                   one of the annexes then it is appropriate to place                                                                                                                                                                                                                            primarily within Module 3 „Quality‟ and
                                                                                                                                   them after the annexes. The „Additional Data‟                                                                                                                                                                                                                                 Module 1 (1.3.1) „Summary of Product
                                                                                                                                   section of Module 1 should not be used except                                                                                                                                                                                                                                 Characteristics, Labelling and Package
                                                                                                                                   for country-specific information.                                                                                                                                                                                                                                             Leaflet‟. Where documents cannot be
                                                                                                                                   The EU M1 specification should therefore be                                                                                                                                                                                                                                   assigned to specific CTD-defined
                                                                                                                                   amended in the next version to reflect this, and a                                                                                                                                                                                                                            locations, then they should be attached
                                                                                                                                   Q&A is required to confirm this, and also to                                                                                                                                                                                                                                  to the 1.2 Application Form. The same
                                                                                                                                   confirm that the same approach should be taken                                                                                                                                                                                                                                approach should be used for renewals. "
                                                                                                                                   for renewals.
                                                                                                                                   March-09 : Interlinking to confirm that referral to                                                                                                                                                                                                                           Recommend that any further
                                                                                                                                   Renewal Guidance is sufficient                                                                                                                                                                                                                                                explanation is placed in the eCTD
                                                                                                                                                                                                                                                                                                                                                                                                                 guidance rather than the specification.


  CR-                        NtA Volume 2B Section The ICH M2 eCTD specification and Notice to Applicants Volume 2B                TIGes 6 March 09 : Principle supported. Action to       Approval date:            Text Included in EU M1 v1.4          TIGes                     Include notes from the Q&A #22 in the EU M1         Update the spec in line with Q&A #22.                                    Recommend that this does not go into
20090126                     2.7.6                 provide different information concerning how to deal with the Synopses          Interlinking Group to progress. Suggested that            1.4.2009                                                                               v1.4.                                                                                                                        the specification (there's no logical
                                                   of Individual Studies in Section 2.7.6. The guidance should be                  option of either hyperlinking to or inclusion of                                                                                                                                                                                                                              place to put it), but into the EU eCTD
                                                   harmonised to provide a similar message in both the CTD and eCTD                synopses.                                                                                                                                        Or should this go in guidance instead?                                                                                       guidance. Essentially, this is providing
                                                   and avoid confusion.                                                            Recommend that the NtA guidance is updated to                                                                                                                                                                                                                                 clarity on how to handle synopses
                                                   The NtA guidance states:                                                        reflect the Section 2.7.6 guidance in the ICH M2                                                                                                                                                                                                                              between Module 2 and Module 5, so it is
                                                   2.7.6 Synopses of Individual Studies                                            eCT                                  Answer: It is                                                                                                                                                                                                                            in essence nothing to do with Module 1.
                                                   The ICH E3 guideline (Structure and Content of Clinical Study Reports)          acceptable either to include copies of the
                                                   suggests inclusion of a study synopsis with each clinical study report,         synopses for each study in Section 2.7.6 or to
                                                   and provides one example of a format for such synopses.                         provide hyperlinks to synopses located in Module
                                                   This section should include the table entitled Listing of Clinical Studies,     5 without providing copies in section 2.7.6. In
                                                   described in guidance for Module 5, followed by all individual study            either case a Listing of Clinical Studies should be
                                                   synopses organised in the same sequence as the study reports in                 provided and this should include hyperlinks to the
                                                   Module 5.                                                                       first page of each synopsis.
                                                   It is expected that one synopsis will be prepared per study for use in all
                                                   regions, and that the same synopsis will be included in this section and
                                                   as part of the clinical study report in Module 5. The length of a synopsis
                                                   will usually be up to 3 pages, but a synopsis for a more complex and
                                                   important study may be longer, e.g. 10 pages. Within the individual
                                                   synopsis, tables and figures should be used as
                                                   appropriate to aid clarity.
                                                   But the ICH M2 eCTD guidance states:
                                                   These synopses should already be located in the Clinical Study
                                                   Reports in Module 5 and should not, therefore, be repeated in
                                                   Module 2. It is considered sufficient to provide hyperlinks from the
  CR-    Bil Ali, Shire      EU Module 1           The description of the use of „COMMON‟ in the specification and                 Propose to clarify the description of the use of      Accepted              Implement in next version of EU M1         TIGes                     Decide on text for clarification of 'Common'        Update the spec to clarify the use of 'common'     See CR-20090506-II    Definition of 'common' updated
20090506 Pharmceticals       Specification v1.3    release notes documents are not clear, and sometimes contradictory.             the 'common' folder in the specification. Also                              specification v1.4.                                                  and include in EU M1 v1.4 spec and examples.        in line with CR 20090506 from Bil Ali, and the                           throughout the document in line with
                                                   E.g., see page 8, 37 and 40 of the specification document, and section          remove screenshots from the specification and                                                                                                                                                        ensuing discussions in the TIGes May.                                    recent TIGes decision:
                                                   2.23 of the release notes.                                                      produce a stand alone document of examples, or                                                                                                                                                       Update the examples p. 37 and 45.                                        "The folder name "common" should only
                                                                                                                                   incorporate these in the eCTD guidance                                                                                                                                                                                                                                        be used for documents applicable to all
                                                                                                                                   document.                                                                                                                                                                                                                                                                     EU countries, irrespective of whether
                                                                                                                                                                                                                                                                                                                                                                                                                 they are receiving the submission or
                                                                                                                                                                                                                                                                                                                                                                                                                 not."
   CR-    Bil Ali, Shire     EU Module 1              The current guidance in the V1.3 M1 specification outlines the use of        Propose to clarify the description of the use of      Accepted              Implement in next version of EU M1         TIGes                     Decide on text for clarification of 'Common'        Update the spec to clarify the use of 'common'     None                  Definition of 'common' updated
20090506- Pharmceticals      Specification v1.3       „COMMON‟ folders with languages, but does not show how specific              the 'common' folder in the specification. Also                              specification v1.4.                                                  and include in EU M1 v1.4 spec and examples.        in line with CR 20090506 from Bil Ali, and the                           throughout the document in line with
    II                                                countries and language combinations should be associated with the            remove screenshots from the specification and                                                                                                                                                        ensuing discussions in the TIGes May.                                    recent TIGes decision:
                                                      use of the „COMMON‟ folder.                                                  produce a stand alone document of examples, or                                                                                                                                                       Update the examples p. 37 and 45.                                        "The folder name "common" should only
                                                                                                                                   incorporate these in the eCTD guidance                                                                                                                                                                                                                                        be used for documents applicable to all
                                                      Whilst this is not a problem when using common folders with the              document.                                                                                                                                                                                                                                                                     EU countries, irrespective of whether
                                                      English „en‟ language, which can apply to all countries, some non                                                                                                                                                                                                                                                                                          they are receiving the submission or
                                                      English languages only apply to specific countries, eg, „de‟ for Belgium,                                                                                                                                                                                                                                                                                  not."
                                                      Germany, and Austria, and „fr‟ for Belgium and France etc.

                                                      Therefore, there may be cases where a „COMMON‟ folder might be
                                                      useful to apply to some languages, such as „de‟, but only for the
                                                      relevant countries.

                                                      Other cases exist for other country / language combinations.

                                                      Is it possible to give clear unambiguous guidance on the combination
                                                      of country, „COMMON‟ folder and language, such that the „COMMON‟
                                                      folders are effectively identified by common languages across multiple
                                                      countries, whilst still maintaining the current use of a „COMMON‟ folder
                                                      with the English language combination across all countries?


                                                      In our view it might be possible to associate specific countries in the
                                                      M1 envelope, with a „COMMON‟ folder and language metadata field to
                                                      give a language related scenario. This should not entail any significant
                                                      change to the specification or to add any additional metadata fields, but
  CR-    Andrew Marr, GSK    EU Module 1              may need a change to the DTD to accommodate it.
                                                      A change request had been received (CR-20070718-01) and                      Remove ATC code from envelope.                        Accepted              Implement in next version of EU M1                                   Remove ATC from envelope in EU m1 v1.4              Remove ATC from envelope.                          Removed "atc" from    Removed "atc" from Appendix 1               Correct mistake p.18 annex
                                                                                                                                                                                                                                                          TIGes
20090517                     Specification v1.3       considered by the Interlinking Group. Although this CR was eventually                                                                                    specification v1.4.                                                                                                                                                         DTD                   Removed "atc" from examples
                                                      rejected it did raise the value of including the ATC code in the Module 1                                                                                                                                                     Minor DTD change.                                                                                      Removed "atc" from
                                                      envelope. It was concluded that the appropriate place for the ATC                                                                                                                                                                                                                                                                    style-sheet
                                                      information was the Application Form and therefore the ATC code in                                                                                                                                                                                                                                                                   Removed "atc" from
                                                      the Envelope was redundant.                                                                                                                                                                                                                                                                                                          examples

                                                      The ATC code should be deleted from the next version of the EU
                                                      Module 1 specification
  CR-    Andrew Marr, GSK    EU Module 1              At FDA there had been problems with processing some sequences                Propose to reduce the maximum fle path length         Accepted              Carry out survey amongst regulators to TIGes                         If tacitly agreed by TIGes, change guidance on      Change maximum file path length to 180                                   The following text has been added to
20090310                     Specification v1.3       provided by applicants because the filepath has been too long and has        from 230 characters to 180. However, a survey                               assess whether 180 is a suitable                                     max. path length to 180 in EU M1 v1.4               characters.                                                              File Naming Convention section:
                                                      been truncated, either in production of hard media or in manipulation        amongst regulators is required to assess                                    maximum file path length for                                                                                                                                                                      "Note that the overall file path length
                                                      across servers within the agency. They proposed that                         acceptability of this maximum length. Consider                              eCTD/NeeS, and if not, what the                                                                                                                                                                   should not exceed 180 characters. "
                                                                                                                                   whether a max. path of 180 should also be                                   maximum reserve required is. If no
                                                                                                                                   implemented in the NeeS design.                                             objection received by 15th june 2009,
                                                                                                                                                                                                               reduce length to 180 characters and
                                                                                                                                                                                                               implement thi
   CR-    Andrew Marr, GSK   EU Module 1                                                                                           Develop regional guidance and include this in the     Accepted - refer to   Develop Q&A on the use of              TIGes                         Include text from Q&A on stylesheets (once          Get QA test on stylesheets form Andrew and                               Appendix 2 (Row 76) updated with the
20090310-                    Specification v1.3                                                                                    next specification version (v1.4).                    Q&A                   stylesheets.                                                         developed) in EU M1 v1.4                            include in spec.                                                         following text:
    II                                                ICH Q&A #50 addresses the inclusion of regional stylesheets It states                                                                                                                                                                                                                                                                                      "The style sheet to be used should be
                                                      that reference should be made to regional guidance on which version                                                                                                                                                                                                                                                                                        the most recent version, which is
                                                      of the regional style sheets should be used. This is not explicitly stated                                                                                                                                                                                                                                                                                 always published as part of the
                                                      in the EU Module 1 spec v1.3. The download package included a new                                                                                                                                                                                                                                                                                          specification package for download. "
                                                      version of the style sheet v1.3 but the text does not state that it should
                                                      be included when Spec 1.3 is used.
                                                      No regional guidance currently exists and should be developed
                                                      It should be clearly stated that the version of the style sheet published
                                                      in the context of each specification version should be used. A Q&A
                                                      should be produced that states this for v1.3. In future the specification
                                                      and any transition guidance should also state this.
                                                                                                                   EU eCTD Specification Change Requests                                                                                                                                                                                                                           ACTION JUNE
   #        Requestor        Specification                                                                                                 Comments                               Status                 Action                   Group Where                            Notes                                     ACTION JUNE                            DTD / Style-                    Specifications                         Comments
                              Component                                                                                                                                                                                           Action is Sitting                                                                                                      sheet Change                        Change
  CR-    Claire Holmes,   EU M1 specification   Analysis is currently underway to ascertain the impact of the new         Changes not known as yet - to be determined in   Open            Assess impact of new variation        TIGes                Changes no identified as yet - sub-group to     1. Include new submission (mode) element         Amended Envelope        Amended Appendix 1                        Still need to provide good
20090603 EMEA             v1.3                  variation regulation coming into force 1st January 2010 on the eCTD. If   a meeting of a dedicated subgroup to be held                     regulation on the eCTD EU M1 in a                          inform EU M1 drafting group as appropriate.     with 3 valid values: Single, Grouping,           DTD                     Extended text under "Envelope"            submission description in
                                                any changes are needed to the eCTD to support the variation               18th June, and another early July.                               dedicated subgroup (already                                                                                Worksharing. Optional number attribute on this   Amended Examples        Extended Annex with examples and          Specifications and in
                                                regulation, these should be implemented and a new v1.4 pu                                                                                  established) and produce changes as                                                                        level to define the worksharing or grouping      Amended Style-sheet     description of the use of the sequence    Examples provided and used.
                                                                                                                                                                                           necessary to spec. and DTD.                                                                                number if needed. Can cover one product or                               and related sequence fields
                                                                                                                                                                                                                                                                                                      multiple products.                               Examples:
                                                                                                                                                                                                                                                                                                      Make submission type repeatable. Retain          1 - CP, single
                                                                                                                                                                                                                                                                                                      lower-level application number.                  2 - NP, single
                                                                                                                                                                                                                                                                                                                                                       3 - DCP, single
                                                                                                                                                                                                                                                                                                      2. Include 6 examples of the use of the          4 - MRP, single
                                                                                                                                                                                                                                                                                                      envelope for single, grouping and worksharing    5 - CP, grouping, MA,
                                                                                                                                                                                                                                                                                                      submissions for one product and across           type
                                                                                                                                                                                                                                                                                                      multiple products. Include these, once           6 - CP, grouping, MA,
                                                                                                                                                                                                                                                                                                      approved, as an annex to the spec.               types
                                                                                                                                                                                                                                                                                                                                                       7 - MRP, grouping,
                                                                                                                                                                                                                                                                                                      3. Include an example of the use of related      MAs, types
                                                                                                                                                                                                                                                                                                      sequence for worksharing.                        8 - MRP, worksharing

                                                                                                                                                                                                                                                                                                      4. Include some examples of the free-text
                                                                                                                                                                                                                                                                                                      submission description, relating to the new
                                                                                                                                                                                                                                                                                                      variation regulation.

                                                                                                                                                                                                                                                                                                      Include other useful examples of the free-text
                                                                                                                                                                                                                                                                                                      'submission description' field.
  CR-    Claire Holmes,   EU M1 specification   Paediatric studies in the context of Article 46 of Regulation (EC) No     Agreed by EMEA                                   Open            Implement in EU M1 v1.4               TIGes                Add new submission type to envelope - 'Art 46'. Add new submission type to envelope - 'Art 46'. Added article-46 in      Article 46 added to table of submission
20090620 EMEA             v1.3                  1901/2006 (The Paediatric Regulation) must be submitted, and these                                                                                                                                                                                                                                    DTD (envelope)           types
                                                afall within the scope of eCTD. A submission type 'Art 46' should                                                                                                                                                                                                                                     Amended style-sheet
                                                therefore be included in the EU M1 specification.                                                                                                                                                                                                                                                     to support article-46
                                                                                                                                                                                                                                                                                                                                                      value
Following the review of EU eCTD Change Request and Questions carried in December 2009, a number of approved
changes were identified that do not alter the technical specification (the DTD) but provide additional clarification on
the use of the specification. Usually, such changes would be saved until a technical specification change becomes
necessary. However, in light of the number of such changes and the importance of the topics that they address, a
proposal has been made to issue an interim update to the EU Module 1 eCTD Specification and Annex documents
that will incorporate these amendments and additions. The proposed version number for these documents will be
v1.4.1. This update will probably be released towards the end 1Q10 or early 2Q10.

Vendors of eCTD building and reviewing tools should note that there is no plan to update the technical
specification/DTD at this time and the v1.4.1 changes will only be clarifications and additions to the wording of the
Specification and Annex documents to improve their usefulness to applicants.

Applicants wishing to submit eCTD submissions should continue to use the v1.4 DTD in accordance with previously
published guidance from the TIGes and EU NCAs. The full transition to the use of the v1.4 DTD from 1st July 2010
is unaffected by this proposal.

In a minor oversight, information identifying the likely changes to be incorporated in the v1.4.1 documentation was
                                                            EU eCTD Specification Change Re
      #               Requestor               Specification
                                              Component
    0018         Alex Yates              eCTD EU Module 1
                 Kendle                  Specification and type
                                         definition




 20060627-02     Bernadette Billet,      EU Module 1 DTD and
                 Liquent                 Specification, v1.2




QA-20061017-01   Hans van Bruggen,       ICH eCTD specs v3.2
                 eCTDConsultancy         Appendix 6


CR-20070405-01   Geoff Williams, Roche   ICH Q&A, Q&A36, item 12
CR-20070426-01   Joe Cipollina, BMS    ich-stf-stylesheet-2-2.xsl




CR-20070426-02   Joe Cipollina, BMS    Valid-values.xml



QA-20070628-04   Thierry Le Ridant,    eCTD EU Module 1
                 Ethypharm             specification v1.2.1

CR-20080903-01   Alastair Nixon, GSK   MRP/DCP Best Practice
                                       Guidance




 CR-20080610     Andrew Marr, GSK      EU eCTD Validation
                                       Criteria




CR-20080610-01   Andrew Marr, GSK      EU eCTD Validation
                                       Criteria
CR-20080610-02   Andrew Marr, GSK         EU eCTD Validation
                                          Criteria




 CR-20080909     Leigh Sandwell, Pfizer   eCTD Guidance
CR-20080903   Alastair Nixon, GSK   EU M1 Specification v1.3




CR-20081210   Gerhardt Neurauter,   EU Validation Criteria
              Extedo
EU eCTD Specification Change Requests Implemented or Closed
                              Description

    Please can you inform us as to the date when the updated
    European Module 1 specifications issued in January 2006
    become mandatory for use in all eCTD submissions in the EU. It
    takes some time to update the system for generating the EU
    Module 1 XML and so this information would be useful. In the
    future, consideration should be given to adding a date for coming
    in to operation to the European Module 1 specifications guideline.

    When migrating the product information from Word to PIM for a
    product managed by an eCTD how should the operations
    attributes be used?

    Version 1.2 DTD allows either a PIM submission or the Word
    documents in 1.3.1, not both. For a product that has previously
    submitted Word PI documents these will be located under 131-
    spc-label-pl but with PIM it will go under 131-pim. As such it is
    not appropriate to use „replace‟ since replace should only be
    used on documents at the same location in the backbone. If
    „new‟ is used for PIM this will still leave the previous Word
    documents as being current. It is not possible to use delete either
    since the specification does not support entry of leafs in both 131-
    pim and 131-spc-label-pl in the same submission. Could
    guidance please be given for how to manage this transition so
    that the PIM information is seen as new and the old Word
    information is seen simultaneously as „not current‟ when a
    current or cumulative view is used?

    Nine Questions on the use of the eCTD in Module 3 of the CTD
    were submitted.


    ICH Q&A36, item 12 says “Ensure all the files identified by an
    xlink:href reference exist”. This should be clarified to state where
    the files can exist.

    The check for item 12 is ambiguous as to where the file identified
    in xlink:href should exist. At the time this was written, we
    probably meant “exist within the same sequence”. However,
    current thinking on the use and reuse of content means that
    content can exist in another sequence within the same
    application or (for the US at least) within a separate application
    Some testing of this was carried out in the ETICS study and the
    results showed that tools were not necessarily sticking to the
    strictest interpretation (within the same sequence). This item
    description should be amended to describe the current use and
    understanding of the xlink:href.
The ICH STF Stylesheet currently posted gives inconsistent
display results in Internet Explorer. It seems to work in some
cases but not in others. STF files which were viewable with the
older version of the stylesheet are no longer always viewable.

There are differences in the values listed in the valid-values file
posted on the ESTRI website and the valid-values file posted on
the FDA website.

DCP or MRP are followed by a national phase (PIL etc.). What
should be the value of the "procedure type" field "national" or
"MRP" ?
The requirement for a cover letter in local language means that
applicants preferring to centralise electronic dossier production,
or following the preferred „Comprehensive model‟ for eCTD in
MRP/DCP must get a cover letter translated into all European
languages before building the dossier. For submissions requiring
an application form, this is unavoidable, since the form contains
details of the MAH, and local contacts etc. However, for follow up
measures, or simple administrative submissions, the requirement
to get a cover letter translated up to 23 times is onerous and
does not add value to the dossier (NB the rest of the content is
likely to be in English). Could a „common‟ English language cover
letter be used for such submissions?




EU validation criterion #37 defines that no file should have been
scanned at a dpi of more than 300. The ETICS testing
demonstrated that it does not appear possible to assess a pdf file
and determine what the scan resolution used to produce the file
actually was. It is proposed that this criterion is deleted.

EU validation criterion #45 refers to EU Q&A as its reference.
This is incorrect as it is ICH Q&A 36 - change reference.
There is an inconsistency between EU validation Criterion #11
and #18 relating to the title field when the delete operation is
used. #11 states „Every leaf or node extension 'title' attribute is
not empty‟. #18 states „If the value of the operation attribute is
delete,……title is not required…..Consistency should be
introduced.
Additionally the wording of #11 could be improved to state “No
leaf or node extension 'title' attribute is empty”
Even if this is changed then there is still inconsistency.
Either – agree that the title should be included when delete is
used – change #18 but this would require a change to ICH
Q&A36 #20
Or – agree that title remains optional and therefore modify #11 to
provide an exception when the delete is used.

Current guidance requires that statements justifying absence of
data in the eCTD should be provided in the QOS, non-clinical
and clinical overviews, as applicable, and that no placeholder
documents are required in the eCTD structure. The guidance
should be updated to clarify how to deal with empty sections of
Module 1 and any potential justification that may be required.
Copy requirements for eCTDs should be different from other
electronic dossiers – all CHMP members should get an
electronic copy of everything, including Type IA/IB variations –
otherwise future lifecycle operators will be invalid.
The current copy requirements do not differentiate between
eCTD and NeeS. For Type IA and IB variations, only the
Rapporteur requires 2 electronic copies,
other CHMP members get nothing. However, a Type IA variation
can amend a significant piece of content in the dossier. For
example, a Category 12a variation to tighten a specification will
modify S4.1. A future Type II variation could result in a
replacement active specification being submitted, but the if the
original change had not been uploaded by an agency, the
modified file in the second change will be invalid. In addition, any
countries not uploading all sequences will get an incorrect
„current view‟ for the application.

So far, the EU Validation Criteria do not verify the correctness of
the overall checksum in the provided index-md5.txt. Guidance is
given by the EMEA to provide this checksum in the cover letter,
however, the possibility to verify the MD5 with the EURSvalidator
is not given.
Authorities not using the EURSvalidator perform checks with
tools verifying the overall checksum. We received responses
from clients that submissions are rejected due to invalid values in
the index-md5.txt. However this issue is not part of the EU
Validation Crieria.
In case of MRP/DCP we encounter troubles that submissions are
accepted only in regions the EURSvalidator is used.
ests Implemented or Closed
                        Comments                       Status   Action

       Addressed by EU M1 v1.3 specification and       Closed   None
       transition plan




       Updated in guidance - Word not to be included   Closed   None
       in the eCTD in any case.




       This CR/Q&A was submitted to the ICH M2         Closed   Discussed at ICH M2,
       group for consideration. It has been added here          see ICH tracking sheet
       for completeness and to record any discussion            for details of outcome.
       and position taken at an EU level.
       This CR/Q&A was submitted to the ICH M2         Closed   Discussed at ICH M2,
       group for consideration. It has been added here          see ICH tracking sheet
       for completeness and to record any discussion            for details of outcome.
       and position taken at an EU level.                       Addressed in EU Q&A 14
                                                                as regional guidance
This CR/Q&A was submitted to the ICH M2         Closed                     Discussed at ICH M2,
group for consideration. It has been added here                            see ICH tracking sheet
for completeness and to record any discussion                              for details of outcome.
and position taken at an EU level.

This CR/Q&A was submitted to the ICH M2         Closed                     Discussed at ICH M2,
group for consideration. It has been added here                            see ICH tracking sheet
for completeness and to record any discussion                              for details of outcome.
and position taken at an EU level.
Response provided in Best Practice guide for    Closed                     None
use of eCTD in MRP/DCP published by CMD(h).

For submissions not requiring an application      Implemented              March 2009 CMD(h)
form, a single „common‟ English language cover                             press release included
letter is acceptable in all MS.                                            statement
Identified as a hurdle for eCTD implementation.
Cover letter is not covered by legislation, but
nevertheless some MS have requirements for
local laguage versions. HMA to try to persuade
individual agencies to relax requirements for a
cover letter in the local language. This should
not be a requirement - one cover letter in EN
should be accepted by all MS. ACTION:
Applicants to inform Interlinknig group of any MS
asking for local language cover letters, and the
group will try to dissuade these MS. Also
indicate if these MS have local letter templates
or are asking for the general cover letter to be
translated. Also include information as to
whether the MS ask for this cover letter to be in
the eCTD.
March-09 : Updated national requirements table
should address but press release will indicate
that there should be no additional national
requirements. Consideration to be given to
identification of point of contact is NCAs
request/require additional national specifics.

                                                Implemented in EU          Implemented in EU
                                                validation criteria v2.0   validation criteria v2.0




Check all references                            Implemented in EU          Implemented in EU
                                                validation criteria v2.0   validation criteria v2.0
Change criterion #18 to indicate that the title      Implemented in EU          Implemented in EU
should be included when delete is used, but          validation criteria v2.0   validation criteria v2.0
included a statement to indicate that this is not
consistent with the ICH criterion #20.
Create an ICH CR to indicate that ICH criterion
#20 should refer to regional guidance.




Recommend that empty Module 1 Sections do     Implemented in      Agreed wording include
not require a justification statement to be   Harmonised Guidance in Harmonised eCTD
included in each section and the Q&A document                     Guidance v1.0
is updated to reflect Module 1.

Approach to M1 is different than for other
modules, as M1 should always be populated
(even with 'not applicable' statements) as a legal
requirement. Another proposal is that only
justifications should be required - simple
statements of not applicable should be included
in the cover letter. Revisit this discussion as
currently no agreement.
March-09 : Principle that empty sections where
no justification for absence is required should be
listed in the Cover Letter. Proposal to provide
statement in Harmonised eCTD Guidance.
Wording to be confirmed by Interlinking Group.
April -09 : decision modified and agreed
statement included in Harmonised guidance -
Section 3.2.1
Electronic copy requirements for Type IA and IB Implemented in new          Dossier requirements
variations are split by NeeS and eCTD. For      dossier requirements        updated April 2009
NeeS, they stay as they are. For eCTD, the
requirements for Type IA and IB variations
mirror those for Type II – i.e. “Other CHMP
members: 1 electronic copy”.




Introduce to the EU Validation Criteria an         Implemented in v2.1      Validation criteria v2.1
additional issue: “The checksum of the             of validation criteria   published
index.xml should be calculated by a validation
tool and compared with the checksum provided
in the index-md5.txt.” In case of invalidity the
recommended severity should be A.
TIGes 6 March 09 : Agreed to progress as an
urgent change and actioned to the EURS group

								
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